1. health and fitness
2. addiction


NEUROBIOLOGICAL
AND
BEHAVIORAL
PHENOTYPES
AND
COCAINE
SELF‐ADMINISTRATION
IN
ADULT
RHESUS
MONKEYS
EXPOSED
TO
COCAINE
THROUGHOUT
GESTATION
B Y
LINDSEY
R.
HAMILTON
A
Dissertation
Submitted
to
the
Graduate
Faculty
of
WAKE
FOREST
UNIVERSITY
GRADUATE
SCHOOL
OF
ARTS
AND
SCIENCES
In
Partial
Fulfillment
of
the
Requirements
For
the
Degree
of
DOCTOR
OF
PHILOSOPHY
Program
in
Neuroscience
August
2010
Winston‐Salem,
North
Carolina
Approved
By:
Michael
A.
Nader,
Ph.D.,
Advisor
____________________________________
Examining
Committee:
Joseph
R.
Tobin,
M.D.,
Chair
____________________________________
Paul
W.
Czoty,
Ph.D.
____________________________________
Anthony
Liguori,
Ph.D.
____________________________________
Linda
J.
Porrino,
Ph.D.
____________________________________
ACKNOWLEDGEMENTS
Although
this
dissertation
will
have
only
my
name
on
the
cover,
a
great
number
of
people
have
contributed
to
its
production.
I
owe
many
thanks
to
all
those
people
who
have
made
this
dissertation
possible.
First
and
foremost,
I
would
like
to
express
my
deepest
gratitude
to
my
advisor,
Dr.
Mike
Nader,
who
has
given
me
the
freedom
to
explore
on
my
own
and,
at
the
same
time,
the
guidance
to
better
refine
my
ideas.
He
has
impressed
upon
me
all
the
important
traits
necessary
to
become
a
behavioral
pharmacologist:
perseverance
(“Stay
the
course!”),
proper
terminology
(“Don’t
call
it
a
DRL
schedule.”),
critical
analysis
(“The
data
are
the
data.”),
and
high
caffeine
intake
(“Is
decaf
coffee
a
reinforcer?”).
I
also
greatly
appreciate
the
people
that
made
coming
to
work
everyday
a
treat,
not
a
chore:
my
labmates
with
whom
I
shared
an
office,
frustrations,
successes,
and
many
great
conversations,
Dr.
Matt
Banks,
Dr.
Jenn
Martelle,
Dr.
Natallia
Riddick,
Rob
Gould,
and
Brandi
Blaylock;
and
my
colleagues
who
trained
me
and
were
always
available
to
assist
me
in
anyway,
Sue
Nader,
Tonya
Calhoun,
Michelle
Icenhower,
Susan
Martelle,
Michael
Coller,
and
Whitney
Wilson.
I
also
would
be
remiss
if
I
did
not
thank
my
presidential
monkeys
who
taught
me
patience
and
always
gave
me
a
good
laugh.
ii
I
am
grateful
to
my
dissertation
committee
for
their
helpful
suggestions,
comments,
critiques,
and
alternate
viewpoints:
Dr.
Paul
Czoty,
Dr.
Tony
Liguori,
Dr.
Linda
Porrino,
and
Dr.
Joe
Tobin.
Finally,
I
wholeheartedly
thank
my
friends
and
family
for
their
support,
patience,
and
love
during
my
graduate
school
years.
My
parents
have
always
been
my
biggest
cheerleaders
and
I
deeply
appreciate
their
belief
in
me.
The
friends
who
make
up
my
extended
family
have
given
me
strength
throughout
difficult
times,
celebrated
with
me
in
happy
times,
and
helped
me
stay
focused
on
completing
this
dissertation.
I
truly
value
their
friendship.
This
research
was
supported
by
Grant
R01
DA
025120,
R37
DA
10584,
and
an
Individual
Predoctoral
National
Research
Service
Award
F31
DA
024485
from
the
National
Institute
on
Drug
Abuse.
iii
TABLE
OF
CONTENTS
PAGE
ACKNOWLEDGEMENTS
ii
LIST
OF
ABBREVIATIONS
v
LIST
OF
TABLES
AND
FIGURES
viii
ABSTRACT
x
CHAPTERS:
I.
Introduction
II.
Characterization
of
the
dopamine
receptor
system
in
adult
86
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
Published
in
Psychopharmacology,
accepted
March
2010
III.
Increased
impulsivity
in
male,
but
not
female,
adult
rhesus
115
monkeys
exposed
to
cocaine
throughout
gestation.
Submitted
to
Psychopharmacology,
April
2010
IV.
Increased
vulnerability
to
self­administer
cocaine
in
adult
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
To
be
submitted
to
Science,
May
2010
156
V.
Discussion
182
1
SCHOLASTIC
VITAE
218
iv
LIST
OF
ABBREVIATIONS
5‐HIAA
5‐hydroxyindole
acetic
acid
5‐HT
Serotonin
ACC
Anterior
Cingulate
Cortex
ANOVA
Analysis
of
Variance
BSID
Bayley
Scale
of
Infant
Development
COMT
Catechol‐O‐methyl
transferase
CSF
Cerebrospinal
Fluid
DA
Dopamine
DAT
Dopamine
Transporter
DVR
Dopamine
E
Embryonic
Day
EDTA
Ethylenediaminetetraacetic
acid
e.g.
Exempli
gratia
or
For
example
FCP
Fluoroclebopride
FR
Fixed
Ratio
HV
Highly
Vulnerable
HVA
Homovanillic
acid
i.e.
id
est
or
That
is
i.m.
Intramuscular
IQ
Intelligence
Quotient
i.v.
Intravenous
v
LV
Low
Vulnerable
MAO
Monoamine
oxidase
MDI
Mental
Development
Index
MRI
Magnetic
Resonance
Imaging
nM
Nanomole
NAc
Nucleus
Accumbens
NBAS
Neonatal
Behavioral
Assessment
Scale
NE
Norepinephrine
NHP
Nonhuman
Primates
NIDA
National
Institute
on
Drug
Abuse
NMDA
N‐methyl‐D‐aspartate
NSDUH
National
Survey
on
Drug
Use
and
Health
OTB
Operant
Test
Battery
PCP
Phencyclidine
PR
Progressive
Ratio
ROI
Region
of
Interest
SAMHSA
Substance
Abuse
and
Mental
Health
Services
Administration
SEM
Standard
Error
of
the
Mean
SN
Substantia
Nigra
Pars
Compacta
TH
Tyrosine
hydroxylase
TO
Timeout
vi
VR
Variable
Ratio
VTA
Ventral
Tegmental
Area
vii
LIST
OF
TABLES
AND
FIGURES
CHAPTER
I
PAGE
Table
1.
Subject
Demographics
CHAPTER
II
40
Figure
1. Distribution
Volume
Ratios
of
[18F]FCP
in
the
104
Caudate,
Putamen,
and
Amygdala
Figure
2. A) Yawning
Elicited
by
Quinpirole
in
Female
Prenatally
Cocaine
Exposed
and
Control
Monkeys
B) Yawning
Elicited
by
Quinpirole
in
Male
Prenatally
Cocaine
Exposed
and
Control
Monkeys
C) Group
Comparison
for
Yawning
Elicited
by
Quinpirole
105
106
Figure
3. Correlation
of
Peak
Yawns
Elicited
by
Quinpirole
and
Maximal
Daily
Dose
of
In
Utero
Cocaine
107
Figure
4. A) Effects
of
SKF
81297
on
Eye‐Blinking
Rates
in
Control
Monkeys
B) Effects
of
SKF
81297
on
Eye‐Blinking
Rates
in
Prenatally
Cocaine
Exposed
Monkeys
C) Group
Comparison
of
the
Effects
of
SKF
81297
on
Eye‐Blinking
Rates
108
109
CHAPTER
III
Table
1.
Comparison
of
CSF
Concentrations
of
5‐HIAA
and
HVA
139
Table
2.
Response
Rates
During
the
Delay
Discounting
Task
140
Figure
1.
A) Latency
to
Touch
a
Novel
Object
Placed
in
the
Home
Cage
B) Grid
Crossings
in
a
Novel
Environment
141
Figure
2.
Number
of
Sessions
to
Extinguish
Food‐Reinforced
Behavior
142
Figure
3.
Representative
Delay
Value
–
Percentage
Choice
for
the
Delayed
Reinforcer
Curves
for
a
Prenatally
Cocaine
Exposed
Monkey
and
a
Control
Monkey
143
Figure
4.
Indifference
Points
on
the
Delay
Discounting
Task
144
viii
Figure
5.
Overall
Impulsivity
Score
Measured
Across
Four
Impulsivity
Measures
CHAPTER
IV
145
Figure
1.
Percentage
of
Monkeys
Reaching
Criteria
to
Acquire
Cocaine
Self‐Administration
at
Various
Doses
of
Cocaine
174
Figure
2.
Amount
of
Cocaine
Intake
Prior
to
Reaching
Criteria
to
Acquire
Cocaine
Self‐Administration
in
Prenatally
Cocaine
Exposed
and
Control
Monkeys
175
Figure
3.
Amount
of
Cocaine
Intake
Prior
to
Reaching
Criteria
to
Acquire
Cocaine
Self‐Administration
in
Highly
and
Less
Vulnerable
Monkeys
176
Figure
4.
A) Comparison
of
Impulsivity
Scores
Between
Highly
and
Less
Vulnerable
Monkeys
B) Peak
Yawns
Elicited
by
Quinpirole
in
Highly
and
Less
Vulnerable
Monkeys
C) Relationship
Between
Peak
Yawns
and
Amount
of
Cocaine
Intake
Prior
to
Reaching
Criteria
to
Acquire
Cocaine
Self‐Administration
177
178
CHAPTER
V
Figure
1.
Representative
Response
Rates
for
Food
and
Drug
Under
an
FR
30
Schedule
of
Reinforcement
185
Figure
2.
Acquisition
and
Maintenance
Cocaine
Dose‐
Response
Curves
for
Prenatally
Cocaine‐Exposed
and
Control
Monkeys
187
Figure
3.
Alterations
in
D2
and
D3
Receptors
Could
Result
in
Similar
FCP
DVRs
in
Prenatally
Cocaine
Exposed
and
Control
Monkeys
200
Figure
4.
Percentage
of
Male
and
Female
Monkeys
Reaching
Criteria
to
Acquire
Cocaine
Self‐Administration
at
Various
Doses
of
Cocaine
206
ix
ABSTRACT
Hamilton,
Lindsey
R.
NEUROBIOLOGICAL
AND
BEHAVIORAL
PHENOTYPES
ASSOCIATED
WITH
VULNERABILITY
TO
COCAINE
SELF‐ADMINISTRATION
IN
ADULT
RHESUS
MONKEYS
EXPOSED
TO
COCAINE
THROUGHOUT
GESTATION
Dissertation
under
the
direction
of
Michael
A.
Nader,
Ph.D.,
Professor
of
Physiology
and
Pharmacology
Maternal
cocaine
addiction
is
a
significant
public
health
problem
yet
the
effects
of
cocaine
use
during
pregnancy
on
long‐term
postnatal
outcomes
have
not
been
well
established.
This
dissertation
utilized
an
animal
model
of
prenatal
cocaine
exposure
in
rhesus
monkeys
to
evaluate
the
long‐term
neuropharmacological
consequences,
behavioral
impulsivity,
and
vulnerability
to
stimulant
self‐administration.
These
adult
monkeys
had
been
exposed
to
cocaine
throughout
gestation
and
were
compared
to
a
population
of
control
monkeys.
In
Chapter
II,
the
dopamine
(DA)
receptor
system
was
characterized
using
several
in
vivo
models.
There
were
no
differences
between
groups
in
D2‐like
receptor
availability,
as
determined
with
positron
emission
tomography
imaging,
or
in
D1‐like
receptor
function,
as
assessed
by
unconditioned
behaviors
elicited
by
an
agonist.
Prenatally
cocaine‐exposed
monkeys
had
higher
D3
receptor
function
compared
to
controls,
as
assessed
by
quinpirole‐elicited
yawning.
Additionally,
a
relationship
was
found
x
between
gestational
cocaine
dose
and
D3
receptor
function,
demonstrating
that
prenatal
cocaine
exposure
had
long‐lasting
neurobiological
effects.
The
studies
in
Chapter
III
examined
several
measures
hypothesized
to
assess
impulsivity.
In
general,
unconditioned
behaviors
did
not
show
differences
in
impulsivity,
while
behaviors
involving
schedule‐controlled
responding
were
more
sensitive.
Overall,
male
prenatally
cocaine‐exposed
monkeys
were
more
impulsive
than
controls
while
there
were
no
differences
in
overall
impulsivity
observed
in
females.
Chapter
IV
was
aimed
at
determining
whether
the
neurobiological
and
behavioral
outcomes
observed
earlier
would
result
in
altered
sensitivity
to
the
reinforcing
effects
of
cocaine.
Prenatally
cocaine‐exposed
monkeys
acquired
cocaine
self‐administration
at
lower
doses
than
controls.
Vulnerability
to
self‐administer
cocaine
was
found
to
be
related
to
an
individual
phenotype
involving
increased
D3
receptor
function
and
increased
impulsivity.
In
conclusion,
the
research
presented
in
this
dissertation
suggests
that
cocaine
use
during
pregnancy
can
have
long‐lasting
neurobiological
and
behavioral
effects.
These
results
indicate
that
a
vulnerable
phenotype
for
cocaine
reinforcement
exists
and
that
prenatal
cocaine
exposure
may
predispose
individuals
towards
this
phenotype
in
adulthood.
Greater
understanding
of
this
phenotype
could
lead
to
identification
of
pharmacological
and
behavioral
targets
for
prevention
and
treatment
of
cocaine
abuse.
xi
CHAPTER
I
INTRODUCTION
COCAINE
ABUSE
Cocaine
is
a
powerful
central
nervous
system
stimulant
that
inhibits
the
synaptic
uptake
of
dopamine
(DA),
norepinephrine
(NE),
and
serotonin
(5‐HT)
by
binding
to
the
transporters
for
these
neurotransmitters
(Benowitz,
1993).
Cocaine
also
activates
the
peripheral
sympathetic
nervous
system
and
has
local
anesthetic
effects
(Krug,
1989).
Physical
and
psychological
symptoms
can
arise
from
both
acute
and
chronic
cocaine
use.
Physical
consequences
include
myocardial
infarctions,
ischemic
complications,
arrhythmias,
seizures,
loss
of
consciousness,
and
migraine
headaches
(Gradman,
1988;
Klonoff
et
al.,
1989;
Romero
et
al.,
2002).
The
acute
behavioral
effects
of
cocaine
use
include
irritability,
impaired
judgment,
aggressiveness,
sexual
disinhibition,
increased
impulsivity,
and
manic
excitement
(Taylor
and
Ho,
1977;
Estroff
and
Gold,
1985;
Hurlbut,
1991;
Das,
1993).
Chronic
use
of
cocaine
has
been
associated
with
somatic
complaints,
depression,
anxiety,
paranoia,
memory
loss,
and
problems
with
executive
function
(Jovanovski
et
al.,
2005;
Minnes
et
al.,
2008).
The
peak
of
the
cocaine
epidemic
in
the
United
States
occurred
in
the
mid‐1980s,
when
about
8
million
Americans
were
using
cocaine
regularly
(Cregler
and
Mark,
1986).
The
1988
National
Household
Survey
on
Drug
Abuse
(NHSDA)
found
that
the
number
of
heavy
cocaine
users
increased
signficantly
from
1985
to
1988
(SAMHSA,
1988).
During
this
3
year
period,
there
was
a
33%
increase
among
those
using
cocaine
once
a
week
or
more
(SAMHSA,
1988).
The
1
number
of
Americans
who
used
cocaine
within
the
preceding
month
was
at
an
all
time
high
of
7.1
million
in
1985
(SAMHSA,
1986)
and
1
in
3
young
adults
reported
using
cocaine
at
least
once
(O’Malley
et
al.,
1991).
Today,
cocaine
use
is
still
widespread
in
the
United
States
with
2.4
million
Americans
confirming
current
cocaine
use
(SAMHSA,
2006).
Additionally,
epidemiologic
data
suggest
that
cocaine
dependence
may
be
growing
in
Western
Europe
and
Africa,
evidenced
by
the
largest
recent
increase
in
cocaine
seizures
(United
Nations,
2007),
making
this
a
global
public
health
problem
as
well.
Cocaine
use
among
females
of
childbearing
age
is
significant
public
health
concern.
The
most
recent
National
Survey
on
Drug
Use
and
Health
(NSDUH)
found
that
in
2006‐2007,
5.6%
of
pregnant
women
ages
15
to
44
reported
using
illicit
substances
in
the
past
month
and
almost
1.0%
reported
current
use
of
cocaine
(SAMHSA,
2008).
Of
all
the
illicit
substances,
cocaine,
second
only
to
marijuana,
remains
one
of
the
most
widely
used
illicit
substances
among
women
during
pregnancy
and
is
commonly
used
concurrently
with
tobacco
and
alcohol
(NIDA,
1996;
SAMHSA,
2006).
In
fact,
in
the
1990s,
typically
up
to
10‐20%
of
live
births
in
some
urban,
primarily
low
socioeconomic
status
areas,
tested
positive
for
cocaine
exposure
(Church
et
al.,
1991;
Kandel
et
al.,
1998;
Wetherington
and
Roman,
1998)
although
it
was
reported
as
high
40%
in
one
study
(Ostrea
et
al.,
1992).
Reports
from
the
most
recent
National
Pregnancy
and
Health
Survey
(NPHS)
estimate
that
45,000
infants
prenatally
exposed
to
cocaine
are
born
annually
(NIDA,
1996).
However,
since
the
NPHS
is
based
on
self‐report,
it
is
likely
that
it
is
an
2
underestimate
of
the
scope
of
the
problem
(Markovic
et
al.,
2000;
Savitz
et
al.,
2002,
Bessa
et
al.,
2010).
Even
with
conservative
estimates,
widespread
use
of
cocaine
in
the
United
States
has
resulted
in
upwards
of
1.5
million
children
prenatally
exposed
to
cocaine,
many
of
whom
are
now
entering
adolescence
or
young
adulthood,
a
time
when
many
experiment
with
drugs
of
abuse.
Young
adolescents
with
parents
who
abuse
drugs
are
2‐3
times
more
likely
to
try
substances
(Newcomb
et
al.,
1983;
Jackson
et
al.,
1997;
Kaplow
et
al.,
2002).
Furthermore,
these
children
are
2‐4
times
more
likely
to
have
developed
a
substance
use
disorder
during
adolescence
(Biederman
et
al.,
2000).
Since
1
in
5
Americans
ages
21‐25
years
old
have
tried
cocaine
at
least
once
in
their
lifetime
(SAMHSA,
2008),
this
is
a
large
public
health
problem
if
prenatal
exposure
to
cocaine
increases
vulnerability
to
drug
dependence.
The
focus
of
the
research
in
this
dissertation
is
on
the
long­term
effects
of
prenatal
cocaine
exposure,
specifically
vulnerability
to
self­administer
drugs
of
abuse.
DOPAMINE
The
behavioral
and
reinforcing
effects
of
cocaine
are
thought
to
be
primarily
mediated
by
the
DA
system
(Roberts
et
al.,
1977,
1980;
Wise,
1984;
Ritz
et
al.,
1987;
Bergman
et
al.,
1989;
Madras
et
al.,
1989;
Kuhar
et
al.,
1991).
DA
neurons
are
widely
distributed
in
the
adult
central
nervous
system
and
DA
3
serves
a
variety
of
functions
in
the
mature
brain,
including
control
of
movement
and
the
regulation
of
endocrine,
cardiovascular,
and
limbic
systems.
DA
is
synthesized
from
conversion
of
L‐tyrosine
into
L‐dopa
by
tyrosine
hydroxylase,
the
rate‐limiting
enzyme.
L‐dopa
is
converted
to
DA
by
activity
of
DOPA
decarboxylase.
DA
receptors
are
characterized
by
an
intracelluar
C‐
terminus
region,
an
extracellular
N‐terminus
region,
and
seven
membrane
spanning
regions.
The
receptors
are
coupled
intracellularly
to
guanine
nucleotide
binding
proteins
that
induce
intracellular
signaling
cascades,
which
can
influence
regulation
of
calcium
and
potassium
channels
on
the
postsynaptic
membrane.
The
DA
receptors
can
be
divided
into
two
superfamilies
based
on
their
pharmacological
profiles
and
sequence
homology:
D1‐like
receptors
and
D2‐like
receptors.
D1‐like
receptors,
including
the
D1
and
D5
receptor
subtypes,
catalyze
the
synthesis
of
cyclic
adenosine
monophosphate
(cAMP)
from
the
action
of
adenylate
cyclase
on
adenosine
triphosphate.
Stimulation
of
D2‐like
receptors,
including
the
D2,
D3,
and
D4
receptor
subtypes,
has
opposite
effects,
inhibiting
cAMP
synthesis
(Kebabian
and
Calne,
1979;
Missale
et
al.,
1998).
DA
transmitter
action
is
terminated
by
re‐uptake
into
the
presynaptic
terminal
by
a
high
affinity
plasma
membrane
dopamine
transporter
(DAT)
and
enzymatically
degraded
by
monoamine
oxidase
(MAO)
or
catechol‐O‐methyl
transferase
(COMT).
There
are
several
major
dopaminergic
pathways.
The
nigrostriatal
tract
consists
of
dopaminergic
neurons
in
the
substantia
nigra
(SN)
pars
compacta
that
terminate
in
the
striatum,
a
major
DA‐containing
area
of
the
brain.
The
4
striatum
is
a
component
of
the
extrapyramidal
motor
system
and
plays
an
essential
role
in
the
coordination
of
locomotor
activity.
The
mesolimbic
and
mesocortical
DA
pathways
are
two
midbrain
dopaminergic
pathways
implicated
in
behaviors
associated
with
motivation,
reward
(both
endogenous
systems
and
drug
abuse),
and
reinforcement.
Both
pathways
begin
in
the
midbrain
ventral
tegmental
area
(VTA)
and
provide
input
to
the
nucleus
accumbens
(NAc)
and
frontal
cortex
(both
medial
prefrontal
(mPFC)
and
anterior
cingulate
(ACC)),
respectively
(Olson
et
al.,
1973).
In
monkeys,
it
has
also
been
observed
that
a
subset
of
VTA
neurons
provide
innervation
to
the
caudate
nucleus
of
the
striatum
(Lynd‐Balta
and
Haber,
1994a,
1994b;
Haber
et
al.,
1995).
It
is
thought
that
stimulation
of
DA
receptors
in
mesolimbic
pathway
is
in
part
responsible
for
the
reinforcing
effects
of
cocaine
(Wise
and
Rompre,
1989;
Volkow
et
al.,
1999).
The
subjective
effects
of
cocaine
are
also
thought
to
be
mediated
through
this
same
pathway
(Di
Chiara
and
Imperato,
1988;
Wise
and
Rompre,
1989;
Wise,
1996).
D1‐
like
receptors
are
positively
coupled
to
adenylyl
cyclase
through
stimulatory
Gα
proteins,
resulting
in
an
increase
in
cAMP
concentrations.
DA
D1
receptors
are
primarily
localized
in
the
nucleus
accumbens,
olfactory
tubercles,
and
the
amygdala,
while
DA
D5
receptors
are
primarily
localized
in
the
hippocampus,
hypothalamus,
and
parafascicular
nucleus.
It
is
thought
that
D1‐
like
receptors
may
play
a
role
in
the
reinforcing
effects
of
cocaine.
Several
groups
have
demonstrated
that
antagonism
of
D1‐like
receptors
results
in
increases
in
cocaine
self‐administration
under
a
fixed‐ratio
(FR)
schedule
of
5
reinforcement
in
rats
(Koob
et
al.,
1987;
Corrigall
and
Coen,
1991;
Hubner
and
Moreton,
1991;
Ranaldi
and
Wise,
2001).
D2‐like
receptors
are
negatively
linked
to
adenylate
cylase
through
inhibitor
Gi/o
proteins
and
stimulation
results
in
inhibition
of
cAMP
concentrations.
These
receptors
are
found
throughout
the
brain
including
the
caudate
nucleus,
putamen,
nucleus
accumbens,
olfactory
tubercles,
and
cerebral
cortex.
A
prominent
role
for
D2‐like
receptors
in
the
reinforcing
effects
of
psychostimulants
has
been
established.
D2‐like
receptor
antagonists
attenuate
the
reinforcing
effects
of
self‐administered
cocaine
(Bergman
et
al.,
1990;
Britton
et
al.,
1991;
Corrigall
and
Coen,
1991;
Hubner
and
Moreton,
1991;
Caine
and
Koob,
1993;
Campbell
et
al.,
1999;
Nader
et
al.,
1999).
Additionally,
Volkow
et
al.
(1999)
determined
that
people
with
low
D2‐
like
receptor
availability
as
assessed
with
positron
emission
tomography
(PET)
found
methylphenidate
to
be
more
pleasant
than
people
with
high
D2‐like
receptor
availability.
Additionally,
cocaine
abusers
have
lower
D2‐like
receptor
availability
compared
to
age‐matched,
non‐drug
abusing
individuals
(Volkow
et
al.,
1993;
Martinez
et
al.,
2004).
Monkey
with
lower
D2‐like
receptor
availability
self‐administer
cocaine
at
higher
rates
than
monkeys
with
higher
D2‐like
receptor
availability
(Morgan
et
al.,
2002;
Nader
et
al.,
2006).
It
appears
that
there
may
be
opposing
effects
of
D1‐like
and
D2‐like
receptors
on
the
reinforcing
effects
of
cocaine.
6
DOPAMINERGIC
RECEPTOR
SYSTEM
DURING
GESTATION
Since
the
focus
of
this
dissertation
is
on
the
long‐term
effects
of
prenatal
cocaine
exposure,
it
is
important
to
understand
the
development
of
the
DA
system
during
gestation.
Tyrosine
hydroxylase
(TH),
the
rate‐limiting
enzyme
in
DA
synthesis,
is
a
useful
marker
for
identifying
DA
neurons.
TH
is
first
apparent
at
Embryonic
day
(E)
12‐13
of
an
approximate
21
day
gestational
period
in
the
rat
midbrain,
and
is
present
by
E14
of
an
approximate
30
day
gestational
period
in
the
rabbit.
DA
is
also
likely
to
have
early
biological
activity
in
the
primate
brain.
In
the
monkey,
DA
neurons
of
the
SN/VTA
are
produced
between
E36
and
E43
of
a
165
day
gestational
period
(Levitt
and
Rakic,
1982).
In
humans,
midbrain
DA
neurons
appear
during
the
first
trimester
in
the
second
month
of
gestation
(Olson
and
Seiger,
1972).
This
input
is
thus
already
present
in
the
cortex
even
while
more
superficial
cortical
layers
(II‐IV)
are
beginning
to
form,
consistent
with
a
morphogenic
role
of
DA.
Axons
of
dopaminergic
cells
reach
the
cortex
a
few
days
after
their
initial
detection
in
the
midbrain
in
monkeys
(Lambe
et
al.,
2000).
Limbic
cortical
regions,
such
as
the
ACC
and
mPFC
receive
the
densest
dopaminergic
innervation.
The
density
of
tyrosine
hydroxylase‐positive
axons
in
the
cortex
increases
gradually
over
development
then
declines
postnatally
to
reach
adult
levels
during
puberty
(Lambe
et
al.,
2000).
Transcripts
for
the
D1,
D2
and
D3
receptors
can
be
detected
in
the
striatum
and
cortex
by
E14
in
the
rat
and
by
E12
in
the
mouse
(Jung
and
Bennett,
1996;
Araki
et
al.,
2007).
D1‐like
and
D2‐like
receptors
are
measurable
7
at
these
early
prenatal
time‐points
and
increase
in
great
quantity
throughout
prenatal
and
early
postnatal
development
to
reach
adult
levels
of
expression
between
postnatal
day
14
and
21
in
rodents
(Sales
et
al.,
1989;
Rao
et
al.,
1991;
Schambra
et
al.,
1994;
Caille
et
al.,
1995).
In
the
monkey,
DA
receptors
appear
in
target
regions
of
DA
input
by
week
12
of
gestation
(Lidow
et
al.,
1991;
Lidow,
1995a)
and
in
humans
DA
receptor
binding
sites
have
been
detected
by
week
twelve
of
gestation
(Aubert
et
al.,
1997).
In
all
species
examined,
DA
receptors
are
present
very
early
in
prenatal
development,
consistent
with
a
role
for
DA
in
regulating
neuronal
differentiation
and
circuit
formation.
Therefore,
the
DA
system
is
a
potential
modulatory
target
for
cocaine
to
act
on
during
prenatal
development
when
the
drug
is
used
during
pregnancy
(Malanga
and
Kosofsky,
2003;
Stanwood
and
Levitt,
2004).
“CRACK
BABIES”
In
the
1980s,
the
'war
on
drugs'
associated
with
the
crack
cocaine
epidemic
focused
national
attention
on
the
relationship
between
drug
use
and
social
and
economic
problems
in
society.
An
early
report
in
The
New
England
Journal
of
Medicine
suggested
that
prenatal
cocaine
exposure
could
cause
behavioral
and
learning
problems
(Chasnoff
et
al.,
1985)
and
a
media
frenzy
over
"crack
babies"
ensued.
Despite
Chasnoff
and
colleagues’
warnings
that
more
research
was
needed
to
determine
the
long‐term
effects
of
prenatal
cocaine
exposure,
media
reports
described
children
exposed
to
cocaine
in
utero
as
a
"bio‐underclass"
and
forecasted
that
"theirs
will
be
a
life
of
certain
suffering,
8
of
probably
deviance,
of
permanent
inferiority”
(Krauthammer,
1989).
The
rising
trends
of
cocaine
use
among
pregnant
women,
coupled
with
these
types
of
dire
reports
in
the
popular
press,
resulted
in
a
rush
to
judgement
with
regard
to
the
fate
of
prenatally
cocaine
exposed
children
(Leshner,
1998).
The
persistence
of
the
mythology
that
prenatally
cocaine‐exposed
children
suffer
from
a
myriad
of
devastating
effects
may
negatively
shape
clinical
investigations.
Observers
of
children
who
are
cocaine‐exposed
may
be
influenced
by
media
reports
that
frequently
over‐generalize
from
anecdotal
descriptions.
Media
anecdotal
descriptions
have
been
used
in
a
manner
that
implies
that
these
children
are
representative
of
all
children
who
are
cocaine‐
exposed
(Neuspiel,
1993;
Day
and
Richarson,
1993;
Elyer
and
Behnke,
1995;
O’Neill
and
Carter,
1999;
Will,
1999;
Rotzoll,
2000).
The
label
cocaine‐exposed
may
then
impact
the
expectations
of
clinicians
and
researchers
working
with
children.
Woods
et
al.
(1998)
designed
a
study
that
examined
the
association
between
the
label
cocaine‐exposed
and
observers’
perceptions.
College
students
from
education,
nursing,
general
education,
and
psychology
programs
were
asked
to
rate
behavioral
parameters
from
videotapes
of
healthy
infants
who
were,
in
fact,
not
cocaine‐exposed.
One
group
of
observers
was
told
that
the
child
they
were
about
to
watch
was
“born
without
any
known
problems.”
A
second
group
was
told
that
the
same
child
was
“born
without
any
known
problems
other
than
that
her
mother
used
cocaine
during
pregnancy.”
The
results
of
the
study
showed
that
the
same
infants
in
the
same
tapes
when
labeled
as
cocaine‐
9
exposed
during
pregnancy
were
rated
more
negatively
than
when
they
had
not
been
labeled
as
cocaine‐exposed.
This
prejudice
is
damaging
in
clinical
settings
and
highlights
the
crucial
need
for
research
on
the
subject
to
be
done
thoroughly
and
without
bias.
Prenatal
cocaine
exposure
in
animal
models
allows
for
such
objective
assessments
across
a
wide
range
of
behaviors.
PRENATAL
COCAINE
EXPOSURE:
HUMAN
STUDIES
Maternal
cocaine
use
during
pregnancy
continues
to
be
of
great
concern
for
health
care
professionals.
It
has
been
suggested
that
gestational
exposure
to
drugs
of
abuse
is
the
single
largest
preventable
cause
of
in
utero
developmental
compromise
of
infants
in
the
United
States
today
(Lester
and
Twomey,
2008).
Findings
in
the
literature
demonstrate
inconsistencies
in
regard
to
the
physiologic
and
developmental
outcomes
of
infants/young
children
prenatally
exposed
to
cocaine.
Further
research
is
warranted,
as
it
is
evident
from
studies
that
not
all
investigators
are
controlling
for
confounding
variables
such
as
poly‐drug
use,
which
is
necessary
in
order
to
isolate
cocaine's
effects.
However,
the
majority
of
research
on
the
topic
points
to
a
myriad
of
clinical
manifestations
that
present
in
the
infant/young
child.
Cocaine
use
during
pregnancy
poses
a
risk
to
both
mother
and
fetus
and
has
been
associated
with
significant
obstetric
complications.
Pregnant
women
who
use
cocaine
have
been
found
to
have
a
higher
incidence
of
poor
weight
gain
and
cardiac
complications,
such
as
hypertension,
arryhythmia,
10
cardiac
ischemia,
and
hemorrhagic
stroke
(Plessinger
and
Woods,
1998;
Kuczkowski,
2003;
Vidaeff
and
Mastrobattista,
2003).
Cocaine
is
known
to
have
a
negative
additive
effect
to
the
already
stressed
cardiovascular
system
of
the
pregnant
woman
(Wagner
et
al.,
1998).
During
pregnancy,
the
toxicity
of
cocaine
is
increased,
thus
increasing
the
risk
for
cardiovascular
events
such
as
stroke
and
seizures
(Plessinger
and
Woods,
1998).
Other
adverse
effects,
including
uterine
rupture,
hepatic
rupture,
placental
abruption
and
maternal
death,
are
known
to
occur
more
frequently
in
those
using
cocaine
(Plessinger
and
Woods,
1998;
Kuczkowski,
2003).
Prenatal
cocaine
exposure
is
hypothesized
to
directly
affect
the
development
of
the
fetal
central
nervous
system
through
teratologic
effects
on
brain
growth
and
development.
The
fetus
is
at
significant
risk
from
cocaine
exposure
secondary
to
maternal
use.
Cocaine
has
a
low
molecular
weight
and
is
both
hydrophilic
and
lipophilic.
These
properties
allow
significant
levels
of
cocaine
to
cross
the
placenta
and
pass
through
the
blood
brain
barrier.
Fetal
cocaine
concentrations
are
equivalent
to
maternal
cocaine
concentrations
within
1‐2
minutes,
raising
fetal
heart
rate,
and
decreasing
internal
and
placental
blood
flow
(Woods
et
al.,
1987).
The
metabolism
of
cocaine
in
the
fetus
is
known
to
be
considerably
slower
than
that
of
the
adult.
Thus,
fetal
exposure
to
cocaine
is
prolonged
(Schenker
et
al.,
1993;
Wagner
et
al.,
1998).
A
study
by
Mahone
and
colleagues
(1994)
found
cocaine
and
its
derivatives
to
not
only
be
transferred
to
the
fetus
via
diffusion
into
the
umbilical
cord
and
within
the
placental
vessels,
but
also
to
be
in
the
amniotic
fluid
and
then
swallowed
by
the
fetus.
In
fact,
11
amniotic
fluid
can
act
as
a
repository
for
cocaine
exposure
to
the
fetus.
Sanberg
and
Olsen
(1992)
demonstrated
that
cocaine
concentrations
in
amniotic
fluid
were
3‐4
times
greater
than
in
fetal
blood.
Cocaine
can
then
enter
the
fetal
blood
at
a
rate
of
3%
from
the
amniotic
fluid
(Mahone
et
al.,
1994).
If
cocaine
enters
the
amniotic
fluid
early
in
pregnancy,
when
water
transport
across
fetal
skin
is
unrestricted,
fetal
exposure
may
be
markedly
enhanced
at
a
critical
time
period
during
which
neurotransmitter
development
is
being
initiated
(Woods,
1998).
The
dose,
the
duration
of
drug
ingestion,
and
the
point
in
gestation
at
which
the
fetus
is
exposed
to
cocaine
determines
the
effect
the
drug
may
have
on
the
fetus.
One
of
the
major
difficulties
in
studying
prenatal
cocaine
exposure
in
humans
is
the
problem
of
controlling
for
confounding
and
moderating
variables.
For
example,
pregnant
women
who
use
cocaine
also
tend
to
use
other
illicit
substances
like
marijuana
as
well
as
licit
substances
that
can
have
toxic
effects
like
nicotine
and
alcohol
(Frank
et
al.,
1988;
Zuckerman
and
Frank,
1989;
Hurt
et
al.,
1995).
There
are
also
many
biological
and
social
confounds
that
must
be
taken
into
account,
including
factors
that
precede
conception
like
maternal
age,
educational
status,
nutritional
status,
and
disease
status
(Frank
et
al.,
1988).
Determining
criteria
for
whether
prenatal
cocaine
exposure
has
occurred
differs
from
study
to
study.
Ascertainment
of
cocaine
use
during
pregnancy
is
commonly
done
by
self‐report,
although
that
is
not
the
most
reliable
method
(Zuckerman
et
al.,
1989).
More
accurate
ascertainment
techniques
include
urine
toxicology
(Ambre
et
al.,
1982;
Weiss
and
Gawin,
1988),
hair
radioimmunoassay
12
(Graham
et
al.,
1989;
Kline
et
al.,
1992),
and
meconium
analysis
(Ostrea
et
al.,
1989;
Lewis
et
al.,
1995).
The
dose
of
cocaine
the
fetus
was
exposed
to
is
also
challenging
to
determine
in
human
studies.
An
interest
in
dose
has
emerged,
though,
as
it
is
thought
that
greater
cocaine
exposure
can
disrupt
brain
development
more
so
and
may
have
greater
behavioral
and
physiological
consequences.
One
issue
in
the
human
literature
is
that
there
is
no
consensus
for
what
defines
heavy
use
of
cocaine
(Frank
et
al.,
1998).
It
is
not
clear
whether
heavy
users
in
one
population
are
comparable
to
heavy
users
in
another
population
because
of
variability
in
potency,
route
of
administration,
and
modes
of
ascertainment
of
dose
of
prenatal
cocaine
exposure.
In
fact,
some
of
the
interviews
designed
to
identify
prenatal
cocaine
exposure
use
a
criteria
of
heavy
use
(using
more
than
two
days
a
week
or
more
than
one
line
of
cocaine
a
day)
that
does
not
distinguish
between
frequency
and
quantity
(Richardson
et
al.,
1993;
Singer
et
al.,
1994;
Jacobson
et
al.,
1996).
Also,
the
dose
used
during
pregnancy
may
vary
throughout
gestation,
as
there
have
been
reports
that
women’s
use
decreases
as
the
pregnancy
progresses
(Richardson
et
al.,
1993).
Beyond
the
issue
of
determining
dose
of
cocaine
exposure,
it
is
not
yet
known
whether
the
primary
determinant
of
adverse
outcomes
is
cumulative
dose
or
maximum
dose
used
on
a
single
occasion
(Frank
et
al.,
1998).
Despite
these
challenges,
it
does
appear
that
there
is
a
cocaine
dose
effect
on
neonatal
size
at
birth,
on
neonatal
behavior,
and
on
infant
informational
processing
(Jacobson
et
al.,
1996;
Hurt
et
al.,
1997;
Chiriboga
et
al.,
1999;
Bateman
and
Chiriboga,
2000).
However,
these
studies
13
need
to
be
more
thoroughly
investigated
while
controlling
for
confounding
biological
and
social
variables.
PHYSIOLOGIC
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
IN
NEONATES
Cocaine's
physiological
effects,
such
as
vasoconstriction,
hypertension,
and
tachycardia
during
pregnancy,
may
have
profound
effects
on
the
fetus.
During
pregnancy,
cocaine
causes
vasoconstriction
of
the
maternal
uterine
blood
vessels
causing
an
increase
in
uterine
vascular
resistance
and
decreased
uterine
blood
flow
(Woods
et
al.,
1987).
Oxygen
and
nutrients
normally
transferred
to
the
fetus
via
these
vessels
are
unable
to
reach
the
placenta
and
fetus
resulting
in
uteroplacental
insufficiency
and
fetal
hypoxemia
(Woods
et
al.,
1987).
This
uterine
vasoconstriction
may
be
the
primary
cause
for
such
complications
as
spontaneous
abortion,
premature
labor
and
delivery,
abruptio
placentae,
and
fetal
intracranial
hemorrhage
(Acker
et
al.,
1983;
Bingol
et
al.,
1987;
Cohen
et
al.,
1991;
Wootton
and
Miller,
1994;
Plessinger
and
Woods,
1998;
Fajemirokun‐
Odudeyi
and
Lindow,
2004).
Although,
one
of
the
metabolites
of
cocaine,
benzoylecgonine,
does
not
cross
the
placenta
very
readily,
the
placenta
is
still
a
direct
target
for
cocaine.
Therefore,
the
placental
transfer
systems
are
adversely
affected
for
essential
nutrients
as
well.
Placental
perfusion
can
be
compromised
by
as
much
as
50%
in
mothers
who
ingest
cocaine
(Woods
et
al.,
1987).
Decreased
14
fetal
oxygen
levels
have
also
been
noted
with
maternal
cocaine
exposure
(Chao,
1996).
In
animal
studies,
a
decreased
level
of
oxygenation
was
not
seen
with
direct
administration
of
cocaine
to
the
fetus
(Chao,
1996).
Therefore,
this
problem
suggests
decreased
oxygenation
results
from
poor
placental
perfusion.
It
has
recently
been
shown
that
cocaine
is
pharmacologically
active
in
the
nonhuman
primate
fetal
brain
(Benveniste
et
al.,
2010).
This
indicates
that
prenatal
cocaine
exposure
may
not
just
have
harmful
effects
on
a
fetus
due
to
placental
circulation
but
also
due
to
cocaine
directly
acting
on
the
developing
brain.
Therefore,
deleterious
effects
of
cocaine
on
brain
development
can
occur
either
directly,
by
influencing
both
structural
and
functional
aspects
of
fetal
brain
development,
or
indirectly,
through
hypoxic
states
which
can
alter
neural
development.
Direct
teratologic
mechanisms
can
affect
the
neurogenesis
of
neural
systems,
including
alterations
on
monoaminergic
system
development
and
neural
growth
factors,
destruction
of
ion
channel
and
monoamine
systems,
and
possible
alteration
of
gene
expression
(Mayes,
2002).
Recent
animal
and
human
imaging
data
have
begun
to
reveal
even
more
specific
areas
of
insult
attributable
to
prenatal
cocaine
exposure.
Lee
et
al.
(2008)
have
isolated
a
mechanism
(down‐regulation
of
the
cell
cycle
regulatory
protein
cyclin
A)
for
the
inhibition
of
neural
progenitor
cell
proliferation
observed
in
fetal
rodents
exposed
to
cocaine
in
utero.
Physiologic
changes
to
15
human
brains
after
fetal
cocaine
exposure
have
been
identified
as
reduced
cerebral
blood
flow
(Rao
et
al.,
2007),
reduced
corpus
callosum
(Singer
et
al.,
2006),
and
smaller
caudate
(Avants
et
al.,
2007)
in
cocaine‐exposed
individuals
compared
to
controls.
Monamines
have
been
the
focus
of
several
studies
as
they
have
a
trophic
influence
on
developing
brain
cells.
Blockade
of
monoamines
may
also
be
a
mechanism
by
which
prenatal
cocaine
perturbs
the
brain
architecture
(Cabrera‐
Vera
et
al.,
2000).
Several
studies
have
examined
areas
of
the
brain
that
are
monoamine‐rich
in
prenatally
cocaine
exposed
animals
and
have
found
evidence
of
alterations
in
brain
cell
development,
including
the
maturation
and
progression
of
brain
development
beyond
the
fetal
period
(Ren
et
al.,
2004;
Morrow
et
al.,
2005;
Lee
et
al.,
2008).
Therefore,
monoamine
circuitry
that
influences
risk‐taking
behavior
and
regulates
substance
use,
emotional
and
behavioral
reactivity
to
stress,
attention,
and
executive
functioning
is
of
particular
relevance
to
the
study
of
prenatally
cocaine‐exposed
adolescence
and
young
adults.
In
Chapter
II,
the
long‐term
effects
of
prenatal
cocaine
exposure
on
the
dopamine
receptor
system
were
examined.
PHYSIOLOGICAL
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
IN
INFANTS
Human
research
involving
very
large
sample
sizes,
multivariate
statistical
analyses,
and
control
for
important
confounds
has
found
consistent
patterns
of
deficit
among
newborns
and
infants
exposed
to
cocaine.
Intrauterine
growth
16
retardation,
prematurity,
low
birth
weight,
and
deficits
in
birth
length
and
head
circumference
for
gestational
age
have
been
consistently
related
to
fetal
cocaine
exposure
in
infants
despite
differing
methodologies
(Singer
et
al.,
1994,
2002;
Chiriboga
et
al.,
1999;
Richardson
et
al.,
1999;
Bateman
and
Chiriboga,
2000;
Kuhn
et
al.,
2000;
Bandstra
et
al.,
2001;
Bada
et
al.,
2002,
2005;
Behnke
et
al.,
2006).
Singer
and
colleagues
(2002)
compared
218
infants
who
were
prenatally
exposed
to
cocaine
to
197
who
were
not
and
reported
that
cocaine
use
during
pregnancy
was
associated
with
an
increase
in
premature
labor
and
delivery,
lower
birth
weight,
smaller
head
circumference,
a
decrease
length
at
birth,
and
shorter
gestational
age.
Similarly,
Bandstra
et
al.
(2001)
noted
cocaine‐
associated
deficits
in
birth
weight
and
length
but
not
head
circumference.
Prematurity
was
not
found
by
Bandstra
et
al.
(2001),
as
the
infants
studied
were
full‐term.
Both
Singer
et
al.
(2002)
and
Bandstra
et
al.
(2001)
included
a
target
population
of
primarily
African‐American
pregnant
women
of
low‐
socioeconomic
status
with
cocaine
use,
identified
confounding
variables
including
poly‐drug
use
(i.e.,
alcohol,
marijuana,
tobacco,
etc.),
and
controlled
for
these
variables
in
comparison
groups.
In
a
study
examining
295
infants
prenatally
cocaine‐exposed
whose
mother
received
no
prenatal
care
as
compared
to
98
infants
whose
mother
did
receive
prenatal
care
by
the
fifth
month
of
pregnancy,
Richardson
et
al.
(1998)
noted
that
during
early
pregnancy
infants
from
both
groups
exhibited
lower
gestational
age,
birth
weight,
length,
and
head
circumference.
The
authors
concluded
prenatal
cocaine
exposure
was
associated
with
restricted
17
intrauterine
growth
regardless
of
prenatal
care.
Confounding
factors
(alcohol,
tobacco,
marijuana,
other
illicit
drugs,
maternal
and
infant
variables)
were
controlled
and
at
the
end
of
each
trimester
both
groups
were
questioned
about
their
use
of
cocaine/crack,
alcohol,
marijuana,
tobacco
and
other
drug
use.
Bateman
and
Chiriboga
(2000)
investigated
the
relationship
between
birth
weight
and
head
circumference
with
the
quantity
of
cocaine
exposure
in
240
non‐randomized
full‐term
infants
from
a
single
inner‐city
hospital.
Levels
of
cocaine
exposure
were
measured
using
radioimmuno
analyses
of
hair
in
the
third
trimester
of
pregnancy.
Measurements
indicated
no
exposure
(136
infants),
low
exposure
(52
infants),
and
high
exposure
(52
infants).
Adjustments
were
made
for
the
confounding
variables
of
use
of
alcohol,
tobacco,
marijuana,
and
opiates
during
pregnancy
as
well
as
infant
and
maternal
characteristics.
A
dose‐response
effect
of
cocaine
on
the
neonates'
head
circumference
was
only
found
in
the
high‐exposure
group.
Chiriboga
et
al.
(1999)
and
Kuhn
et
al.
(2000)
reported
similar
findings.
Chirboga
et
al.
(1999)
also
found
a
decrease
in
birth
lengths
among
infants
prenatally
exposed
to
cocaine
at
high
levels
of
exposure.
In
summary,
research
indicates
prenatal
exposure
to
cocaine
may
affect
the
infant's
gestational
age
at
birth,
length,
weight,
and
head
circumference.
As
described
in
more
detail
later
in
this
chapter,
the
prenatally
cocaine
exposed
monkeys
used
in
this
dissertation
showed
decreased
infant
body
weight,
body
length,
and
crown
circumference
at
birth
compared
to
controls
(Morris
et
al.,
1997).
18
However,
there
were
no
differences
in
postnatal
growth
of
the
offspring
over
the
first
18
months
between
the
two
groups
(Morris
et
al.
1996).
The
mean
weight
of
the
two
groups
has
not
been
different
since
12
months
of
age.
NEUROBEHAVIORAL
AND
NEUROLOGICAL
OUTCOMES
In
infants
and
preschoolers,
a
pattern
of
neurocognitive
processes
(Azuma
et
al.,
1993;
Mayes
et
al.,
1993;
Jacobson
et
al.,
1996;
Lester
et
al.,
1998;
Singer
et
al.,
2000)
has
been
shown
to
be
negatively
affected
by
fetal
cocaine
exposure
in
the
domains
of
attention
(Singer
et
al.,
2000;
Gaultney
et
al,
2005),
arousal
modulation
(Morrow
et
al.,
2001;
Mayes,
2002),
cognitive
and
language
processing
(Alessandri
et
al.,
1993;
1998;
Singer
et
al.,
2001;
Morrow
et
al.,
2003;
Lewis
et
al.,
2004),
and
tone
and
motor
function
(Arendt
et
al.,
1999).
However,
some
of
these
neurobehavioral
reports
are
conflicting.
In
an
early
study,
Mayes
et
al.
(1993)
administered
the
Brazelton
Neonatal
Behavioral
Assessment
Scale
(NBAS)
to
56
newborns
(24‐48
hours
old)
prenatally
exposed
to
cocaine
and
20
matched
newborns
who
were
not
exposed.
The
authors
found
the
infants
prenatally
cocaine‐exposed
only
demonstrated
a
lower
score
on
the
habituation
cluster
of
the
NBAS,
which
indicates
that
the
infants
required
more
stimulus
exposures
before
they
demonstrated
a
decreased
response
to
that
stimulation.
A
1995
study
examined
the
association
between
61
3‐month‐old
infants
prenatally
exposed
to
cocaine
and
47
non‐exposed
infants
(Mayes
et
al.,
1995).
Controlling
for
poly‐drug
use,
the
authors
documented
no
19
difference
in
informational
processing
by
habituation
and
response
to
novelty
related
to
prenatal
cocaine
exposure
assessed
by
a
visual
habituation
and
novelty
responsiveness
procedure.
A
retrospective
study
found
464
infants
heavily
exposed
to
cocaine
prenatally
to
have
poorer
scores
on
the
novelty
preference
test
at
6.5
and
12
months
and
faster
reactivity
on
the
visual
expectancy
paradigm
at
6.5
months
(Jacobson
et
al.,
1996).
While
examining
neonates
prenatally
cocaine‐exposed,
Morrow
et
al.
(2001)
and
Delaney‐Black
et
al.
(1996)
found,
after
controlling
for
covariates,
significant
differences
in
all
NBAS
cluster
scores.
However,
Morrow
et
al.
(2001)
found
no
difference
in
abnormal
reflexes
and
Delaney‐Black
et
al.
(1996)
reported
no
difference
in
habituation
in
the
neonates
prenatally
cocaine‐exposed.
Delaney‐Black
et
al.
(1996)
also
found
infants
with
higher
meconium
concentrations
of
cocaine
metabolites
had
poorer
motor
skills
and
regulation
of
state.
Tronick
et
al.
(1996)
examined
251
full‐term
infants
prenatally
cocaine‐exposed
and
found
poorer
regulation
arousal
(state
regulation
and
excitability)
among
only
the
infants
"heavily"
cocaine‐exposed
at
3
weeks,
but
not
at
3
days
of
age
on
the
NBAS
while
controlling
for
covariates.
Infants
heavily
cocaine‐exposed
were
also
found
by
Singer
et
al.
(2000)
to
be
four
times
as
likely
to
be
"jittery"
and
have
more
movement
and
tone
abnormalities
and
sensory
asymmetries
than
the
lightly
or
non‐exposed
neonates.
The
authors
statistically
controlled
for
other
drug
exposures.
20
King
et
al.
(1995)
found
neurobehavioral
abnormalities
(increased
jitteriness,
hyperactive
responses,
and
excessive
sucking)
on
day
1
and
2
of
life
in
neonates
exposed
to
cocaine
in
utero,
even
while
controlling
for
confounding
variables.
While
King
et
al.
(1995)
identified
these
results
as
consistent
with
withdrawal,
a
report
from
the
American
Academy
of
Pediatrics
(1998)
suggested
that
these
signs
of
neurobehavioral
and
neurological
alterations
were
a
result
of
the
toxic
effects
of
cocaine
itself
rather
than
evidence
of
withdrawal.
Overall,
it
does
appear
that
prenatally
cocaine‐exposed
infants
have
deficits
in
arousal
and
novelty
responsiveness.
In
this
dissertation,
several
models
of
impulse
control,
including
reaction
to
novelty,
were
examined
in
adult
monkeys
prenatally
cocaine
exposed
to
cocaine
and
controls
(Chapter
III).
COGNITION
The
results
of
studies
to
determine
an
association
between
a
cognitive
delay
and
prenatal
cocaine
exposure
are
conflicting.
Several
studies
documented
no
statistically
significant
differences
on
cognitive
development
assessed
by
the
Bayley
Scale
of
Infant
Development's
(BSID)
Mental
Development
Index
(MDI)
among
infants/young
children
exposed
to
cocaine
prenatally
when
tested
at
6‐24
months
(Jacobson
et
al.,
1996;
Kilbride
et
al.,
2000;
Frank
et
al.,
2002;
Messinger
et
al.,
2004).
21
Similarly,
Koren
et
al.
(1998)
investigated
the
intelligence
quotient
(IQ)
of
2
1/2‐year‐old
children
prenatally
cocaine‐exposed
(n
=
23)
and
adopted
at
birth
into
middle
to
upper
class
families
to
a
control
group
(n
=
23).
The
authors
claim
that
their
design
provided
exclusion
of
postnatal
environment
influences
on
the
cognitive
functioning
of
infants
prenatally
exposed
to
cocaine.
After
administering
the
Bayley
and
McCarthy
IQ
tests,
they
found
no
differences
in
global
IQ
between
the
two
groups;
however,
they
reported
a
trend
towards
lower
IQ
of
the
children
in
the
cocaine‐
exposed
group.
In
contrast,
Singer
and
colleagues
(2002)
reported
infants
prenatally
exposed
to
cocaine
were
twice
as
likely
to
have
significant
cognitive
delays
throughout
their
first
2
years
of
life
than
non‐exposed
infants.
Alessandri
et
al.
(1998)
and
Lewis
et
al.
(2004)
reported
lower
MDI
scores
among
infants/young
children
heavily
prenatally
cocaine‐exposed.
Alessandri
and
colleagues
(1998)
examined
the
cognitive
functioning
of
infants
prenatally
cocaine‐exposed
(heavily
exposed
[n
=
30)
and
lightly
exposed
[n
=
30]
to
a
matched
control
group
[n
=
169]
at
8
and
18
months
of
age)
using
the
BSID’s
MDI.
They
documented
a
decrease
in
MDI
scores
only
at
18
months
of
age
among
all
infants
prenatally
cocaine
exposed,
but
the
infants
heavily
exposed
had
the
poorest
scores.
Lewis
and
associates
(2004)
examined
the
effects
of
prenatal
cocaine
exposure
and
cognitive
development
at
12,
18,
24,
and
36
months
of
147
young
children
who
were
exposed
and
89
who
were
not.
After
controlling
for
confounding
factors
such
as
socioeconomic
status
and
maternal
educational
22
level
and
using
the
BSID’s
MDI,
the
authors
found
the
young
children
with
higher
meconium
concentrations
of
cocaine
metabolites
had
lower
test
scores
with
a
decline
at
18
months
on
mental
development.
With
regard
to
older
children,
prenatal
cocaine
exposure
appeared
to
result
in
more
specific
rather
than
general
cognitive
effects.
For
example,
seven
year
old
prenatally
cocaine
exposed
children
were
determined
to
be
2.8
times
more
likely
to
experience
learning
disabilities
than
control
subjects
(Morrow
et
al.,
2006).
Singer
and
colleagues
found
that
prenatally
cocaine
exposed
children
at
ages
4
and
9
years
old
performed
more
poorly
on
tasks
requiring
visual
perceptual
reasoning
than
non‐cocaine
exposed
children
despite
no
Full
Scale
IQ
differences
between
groups
(Singer
et
al.,
2004;
Singer
et
al.,
2008).
Additionally,
decreased
visual
motor
skills
(Arendt
et
al.,
2004),
visual
spatial
working
memory
(Schroder
et
al.,
2004;
Mayes
et
al.,
2007),
and
deficits
in
visual
spatial
integration
(Singer
et
al.,
2004)
have
been
observed
in
prenatally
cocaine‐
exposed
children.
While
not
examined
in
this
dissertation,
both
groups
of
monkeys
will
be
studied
in
cognition
tasks
in
the
coming
years.
ATTENTION/EXECUTIVE
FUNCTION
Attention
and
executive
function
domains
have
been
extensively
investigated
in
prenatally
cocaine
exposed
children
and
a
pattern
of
difficulties
with
sustained
and
selective
attention
(Bandstra
et
al.,
2001;
Savage
et
al.,
2005;
Linares
et
al.,
2006)
have
been
revealed.
In
studies
of
selective
attention,
children
exposed
to
cocaine
prenatally
made
more
commission
errors
(Noland
23
et
al.,
2005)
and
omission
errors
(Accornero
et
al.,
2007)
compared
to
controls.
The
Stroop
Task
has
been
used
to
investigate
executive
function
in
these
children
as
well.
Prenatally
cocaine
exposed
children
generated
longer
responses
to
words
in
this
task
than
non‐exposed
children,
suggesting
that
early
cocaine
exposure
may
inhibit
the
specialization
and
efficiency
of
frontal
functioning
(Mayes
et
al.,
2005).
At
the
age
of
four
years
old,
increased
rates
of
commission
errors,
which
indicate
greater
impulsivity,
were
found
using
an
adapted
version
of
the
Connors’
Continuous
Performance
Test
(Minnes
et
al.,
2010).
In
the
same
cohort
at
6
years
old,
the
prenatally
cocaine
exposed
children
were
reported
to
demonstrate
more
symptoms
of
inattention
than
a
control
group
(Linares
et
al.,
2006).
ANTISOCIAL/AGGRESSIVE
BEHAVIOR
Behavioral
problems
have
been
reported
in
prenatally
cocaine‐exposed
children
in
several
large
well‐controlled
studies.
Studies
using
a
variety
of
measures
including
self
report
(Linares
et
al.,
2006),
caregiver
report
(Sood
et
al.,
2005;
Accornero
et
al.,
2006;
Warner
et
al.,
2006;
Bada
et
al.,
2007;
Minnes
et
al.,
2008),
teacher
report
(Delaney‐Black
et
al.,
2000;
Nordstrom
Bailey
et
al.,
2005),
or
a
combination
(Bendersky
et
al.,
2006),
have
revealed
a
pattern
of
behavior
disturbances
involving
inhibitory
control,
externalizing,
aggressive
and
delinquent
behavior
problems
with
specific
gender
effects
revealed
in
some
studies
(Delaney‐Black
et
al.,
2000;
2004;
Nordstrom
Bailey
et
al.,
2005;
Sood
et
al.,
2005;
Bendersky
et
al.,
2006;
Minnes
et
al.,
2008).
For
example,
with
regard
24
to
impulsivity,
Bendersky
and
Lewis
(1998)
found
that
2
year‐old
prenatally
cocaine‐exposed
children
had
less
impulse
control
compared
to
those
exposed
to
other
substances
but
not
cocaine
in
utero.
Children
were
seated
at
a
table
upon
which
an
experimenter
had
placed
a
cookie
and
were
told
not
to
take
the
cookie
until
the
experimenter
returned.
The
experimenter
gave
the
child
a
novel
toy,
left
the
room,
and
retuned
after
two
minutes.
It
was
found
the
prenatally
cocaine
exposed
children
had
shorter
latencies
to
reach
for,
to
take,
and
to
eat
the
cookie
compared
to
controls
(Bendersky
and
Lewis,
1998),
indicating
that
gestation
cocaine
exposure
alters
impulse
control.
However,
there
have
been
a
limited
number
of
studies
that
found
either
no
differences
(Accornero
et
al.,
2006)
or
attributed
the
negative
behavioral
findings
to
poor
environments,
maternal
psychopathology,
gestational
weaknesses,
and/or
environmental
lead
exposure
rather
than
the
direct
effects
of
cocaine
(Accornero
et
al.,
2002;
Warner
et
al.,
2006).
Early
research
focusing
on
caregiver
reports
indicated
higher
rates
of
behavioral
problems
in
children
prenatally
exposed
to
cocaine
compared
to
non‐
cocaine‐exposed
children
(Richardson,
1998;
Chasnoff
et
al.,
1998).
Several
studies
have
recently
found
an
increase
in
hyperactivity
and
externalizing
behaviors
in
prenatally
cocaine‐exposed
children
(Linares
et
al.,
2006;
Bendersky
et
al.,
2006).
These
behavioral
issues
appear
to
be
exaggerated
in
male
children
exposed
to
cocaine
in
utero,
with
prenatally
cocaine‐exposed
boys
often
demonstrating
more
aggression,
hyperactivity,
and
disruptive
behavior
than
non‐exposed
boys,
whereas
girls
do
not
show
these
differences
(Bendersky
25
et
al.,
2006;
Bennett
et
al.,
2007;
Delaney‐Black
et
al.,
2004).
However,
a
recent
study
indicates
the
increased
odds
of
delinquent
behavior
associated
with
prenatal
cocaine
exposure
to
be
found
only
in
girls
(Minnes
et
al.
2010).
This
discordance
with
earlier
studies
has
been
attributed
to
a
trend
towards
greater
ease
of
reporting
antisocial
and
aggressive
behavior
among
females,
especially
among
those
known
to
be
at
some
biologic
risk
such
as
prenatal
cocaine
exposure.
In
summary,
important
patterns
of
differences
have
emerged
between
prenatally
cocaine‐exposed
children
and
controls
in
human
cohort
studies.
Developmental
differences
have
been
well
documented
and
include
deficits
from
prenatal
cocaine
exposure
on
visual
recognition
and
memory
(Singer
et
al.,
1999;
2005),
attention
(Singer
et
al.,
2000;
Noland
et
al.,
2005;
Linares
et
al.,
2006),
birth
outcomes
(Singer
et
al.,
2002),
early
cognitive
and
language
development
(Singer
et
al.,
2001;
2002),
perceptual
reasoning
(Singer
et
al.,
2004;
2008),
and
aggression/impulse
control
(Linares
et
al.,
2006).
The
differences
that
have
been
observed
between
prenatally
cocaine
exposed
children
and
non‐exposed
children
have
meaningful
implications.
While
the
developmental
outcomes
in
which
differences
have
been
found
in
the
human
cohort
studies
have
small
to
moderate
effect
sizes
(ranging
from
0.2‐0.5),
these
differences
continue
to
be
observed
as
a
consistent
pattern
of
deficits
attributed
specifically
to
prenatal
cocaine
exposure.
Additionally,
it
has
been
reported
that
even
small
differences
and
subtle
effects
have
been
shown
to
result
in
a
substantial
number
of
cocaine‐
26
exposed
children
requiring
special
education
or
therapeutic
intervention
(Lester
et
al.,
1998).
To
date,
there
are
no
studies
that
have
documented
the
persistence
of
early
cognitive
impairment
and
behavioral
problems
due
to
prenatal
cocaine
exposure
through
the
adolescent
and
young
adult
period.
Yet
significant
disruption
in
prenatal
neuronal
differentiation
and
in
the
development
of
neuronal
circuitry
and
anatomy
(Dow‐Edwards
et
al.,
2006;
Singer
et
al.,
2006)
can
have
permanent
effects
on
long‐term
outcomes.
Additionally,
some
long‐
term
outcomes,
like
substance
abuse
and
mental
illness,
may
not
emerge
until
later
in
life.
It
is
hypothesized
that
behaviors
such
as
impulsivity,
sensation
seeking,
and
cognitive
impairments
in
decision‐making
may
manifest
in
adolescence
and
young
adulthood
in
such
activities
as
drug
abuse,
risky
sexual
behaviors,
criminality,
teen
pregnancy,
and
school
drop‐out.
For
example,
some
cognitive
effects
of
prenatal
cocaine
exposure
may
not
appear
until
these
children’s
cognitive
abilities
along
certain
dimensions
are
challenged
as
they
advance
in
their
schooling.
If
pervasive
compensatory
adjustments
occur
for
the
impact
of
prenatal
cocaine
exposure,
there
may
be
substantial
recovery
in
any
compromised
brain
systems
allowing
for
retention
or
return
of
function.
However,
a
long‐term
cost
of
such
compensatory
neural
reorganization
may
be
a
decrease
in
adaptability
(Hughes
and
Sparber,
1978;
Spear,
1996).
Some
behavioral
and
physiological
functions
may
appear
normal
under
basal
testing
conditions
and
deficits
may
only
become
unmasked
when
these
rectified
neural
systems
are
taxed
by
stressors
or
other
challenges.
For
example,
self‐regulating
27
problems
observed
in
infants
and
children
prenatally
cocaine
exposed
may
be
early
markers
for
the
development
of
mental
health
concerns,
not
apparent
until
onset
of
drug
use
or
stressful
transitions
associated
with
adolescent
development.
Central
to
the
problem
of
risk‐taking
behavior
among
prenatally
cocaine‐
exposed
adolescents
and
young
adults
is
whether
it
is
related
to
predisposition
toward
drug
seeking
and
addiction
in
this
group.
Research
efforts
that
identify
early
risk
and
protective
factors
for
substance
dependence
among
prenatally
cocaine‐exposed
children
can
ultimately
prevent
human
suffering
and
reduce
public
health
expenditures.
It
can
also
be
argued
that
the
patterns
of
differences
found,
rather
than
the
number
of
differences
found,
have
important
implications
for
disruptions
in
adult
behavior.
For
example,
attention
and
externalizing
behavior
problems
have
consistently
been
found
among
prenatally
cocaine‐
exposed
children.
This
pattern
of
behavior
has
been
associated
with
the
development
of
substance
use
disorders
and
conduct
problems.
Research
efforts
focusing
on
examining
group
differences
in
substance
use
risk
and
protective
factors
among
prenatally
cocaine
exposed
adolescence
and
young
adults
help
provide
a
foundation
for
prevention
and
intervention
of
drug
abuse.
Currently,
the
human
cohort
studies
have
only
followed
the
prenatally
cocaine‐exposed
children
and
non‐exposed
controls
through
age
13
years.
It
is
not
yet
known
whether
prenatal
cocaine
exposure
is
associated
with
increased
risk
of
specific
types
of
substance
dependence,
mental
health
problems,
or
other
high‐risk
behaviors.
Additionally,
researchers
with
humans,
unlike
those
using
animal
28
models,
struggle
to
refine
their
methods
to
ascertain
accurately
whether
cocaine
exposure
occurred
as
well
as
to
determine
gestational
timing
of
exposure,
the
acute
and
cumulative
doses
to
which
the
fetus
was
exposed
to,
and
to
control
other
potentially
confounding
variables.
Therefore,
the
studies
in
this
dissertation
investigating
the
long­term
effects
of
prenatal
cocaine
exposure
on
risk
factors
for
drug
abuse
in
adult
monkeys
offer
an
important
complement
to
the
human
studies.
PRENATAL
COCAINE
EXPOSURE:
ANIMAL
STUDIES
Paralleling
the
human
longitudinal
studies,
the
animal
literature
indicates
that
prenatal
cocaine
exposure
has
persistent,
specific,
negative
effects
on
brain
anatomy,
organization,
and
neurotransmitter
function.
Learning,
memory,
attention,
emotional
reactivity
to
stress,
and
vulnerability
to
substance
abuse
have
been
investigated
in
prenatally
cocaine‐exposed
animals.
Different
animal
models,
designed
to
mimic
human
drug
use
during
gestation,
confirm
that
prenatal
cocaine
exposure
results
in
specific
and
long‐lasting
behavioral,
cellular,
and
molecular
changes
(Mayes,
2002;
Lidow,
2003;
Harvey,
2004;
Stanwood
and
Levitt,
2004).
However,
the
extent
and
nature
of
the
cellular
alterations
vary
across
model
systems.
Deficits
range
from
alterations
in
basic
processes
of
neocortical
development
that
result
in
altered
cell
production,
migration,
and
genetic
regulation
(Lidow,
1995a,
1995b;
Lidow
and
Song,
2001a,
2001b;
Crandall
et
al.,
2004;
Ren
et
al.,
2004;
Guerriero
et
al.,
2005;
Lee
et
al.,
2008;
Novikova
et
al.,
2008),
to
more
subtle
changes
in
cellular
morphology,
and
molecular
signaling
cascades
within
DA‐rich
regions
of
the
cerebral
cortex
29
(Jones
et
al.,
1996;
2000;
Stanwood
et
al.,
2001;
Stanwood
and
Levitt,
2003;
2007).
Molecular
analyses
have
determined
that
the
DA
D1
receptor
exhibits
permanent
reduced
coupling
to
its
G‐protein
following
prenatal
cocaine
exposure
(Wang
et
al.,
1995;
Friedman
et
al.,
1996;
Jones
et
al.,
2000).
This
reduction
in
coupling
is
a
result
of
DA
D1
receptor
remaining
internalized
and
not
trafficking
properly
to
the
cell
membrane
(Stanwood
and
Levitt,
2007).
Adult
rabbits
exposed
to
cocaine
prenatally
also
exhibit
greatly
reduced
psychostimulant‐induced
stereotypies,
consistent
with
diminished
D1
receptor
signaling
(Simansky
and
Kachelries,
1996;
Stanwood
and
Levitt,
2003).
It
is
important
to
emphasize
that
other
receptor
signaling
does
not
appear
to
be
altered,
nor
is
D2
coupling
altered
in
the
DA‐rich
brain
regions
(Wang
et
al.,
1995;
Friedman
et
al.,
1996).
This
selective
reduced
coupling
of
the
D1
receptor
has
been
implicated
in
the
cellular,
morphological,
and
behavioral
changes
observed
following
prenatal
cocaine
exposure
in
this
teratologic
model.
Additional
evidence
to
support
a
role
for
altered
D1
receptor
signaling
at
the
cellular
level
comes
from
studies
of
the
D1
receptor
knockout
mouse,
which
exhibits
similar
cellular
and
morphological
changes
to
the
prenatal
cocaine
exposed
rabbits
(Stanwood
et
al.
2005).
In
contrast
to
the
relatively
few
cellular
effects
detected,
consistent
behavioral
changes
including
deficits
in
attention
tasks,
emotional
reactivity,
and
the
reinforcing
effects
of
drugs
of
abuse
that
correspond
with
the
human
clinical
literature
are
observed
in
a
variety
of
animal
models
of
prenatal
cocaine
30
exposure
(Morrow
et
al.,
2002;
Rocha
et
al.,
2002;
Gabriel
et
al.,
2003;
Stanwood
and
Levitt,
2003;
Thompson
et
al.,
2005;
Malanga
et
al.,
2008).
Prenatally
cocaine
exposed
rodents
were
found
to
have
long‐term
alterations
in
working
memory,
spatial
memory
(Inman‐Wood
et
al.,
2000),
non‐spatial
short‐term
memory
(Morrow
et
al.,
2002),
and
learning
impairments
in
a
water‐maze
test
(Bashkatova
et
al.,
2005).
Additional
evidence
for
enduring
effects
of
prenatal
cocaine
exposure
in
rats
on
visual
attention
(Gendle
et
al.,
2004)
and
sustained
attention
(Gendle
et
al.,
2003)
can
be
found
in
the
animal
literature.
In
response
to
environmental
or
social
stress,
prenatally
cocaine‐exposed
rats
have
shown
suppressed
levels
of
play
(Wood
et
al.,
1994),
less
behavioral
adaptation
(Campbell
et
al.,
2000),
and
more
aggressive
behavior
(Wood
and
Spear,
1998).
Increased
aggression
(Johns
et
al.,
1994;
McMurray
et
al.,
2008)
and
anxiety
with
decreased
socialization
(Overstreet
et
al.,
2000)
as
well
as
alterations
in
regulatory
and
coping
behavior
with
elevated
responsivity
to
acute
and
chronic
stress
(Wood
et
al.,
1994;
1995)
has
been
observed
in
prenatally
cocaine‐
exposed
rodents.
Prenatally
cocaine‐exposed
rodents
also
show
an
altered
propensity
to
become
involved
in
self‐administration
of
drugs
or
respond
differently
to
cocaine
than
rodents
not
exposed
to
cocaine
(Heyser
et
al.,
1992a,
1992b;
Keller
et
al.,
1994,
1996;
Hecht
et
al.,
1998;
Rocha
et
al.,
2002;
Crozatier
et
al.,
2003;
Guerriero
et
al.,
2005;
Malanga
et
al.,
2009),
raising
questions
regarding
increased
sensitivity
to
drugs
and
increased
substance
abuse
risk
for
prenatally
cocaine‐exposed
humans.
Kosofsky
and
colleagues
have
documented
that
31
prenatally
cocaine‐exposed
mice
do
not
habituate
to
novelty
and
in
response
to
repeated
cocaine
injections,
show
blunted
locomotor
sensitization,
increased
stereotypic
behavior,
and
increased
DA
release
in
the
nucleus
accumbens
(Crozatier
et
al.,
2003;
Guerriero
et
al.,
2005;
Malanga
et
al.,
2009).
This
suggests
that
prenatal
cocaine
exposure
alters
the
adaptation
of
brain
reward
systems
to
chronic
psychostimulant
exposure
in
adulthood.
Other
groups
have
examined
in
rodents
the
reinforcing
effects
of
cocaine
in
adulthood
following
prenatal
cocaine
exposure.
Heyser
et
al.
(1992a,
1992b)
found
that
prenatally
cocaine‐exposed
rats
did
not
acquire
cocaine
conditioned
place
preference
suggesting
a
reduction
in
cocaine
reward.
In
contrast,
Keller
et
al.
(1994,
1996)
determined
that
prenatally
cocaine‐exposed
rats
had
higher
basal
DA
levels
and
had
significantly
higher
rates
of
responding
compared
to
controls
for
a
low
dose
of
cocaine
made
available
under
a
FR
1
schedule
of
reinforcement.
The
dose
of
cocaine
was
actually
so
low
that
it
did
not
appear
to
function
as
a
reinforcer
in
control
animals
(Keller
et
al.,
1996).
In
an
important
control
to
this
study,
no
differences
were
observed
in
acquisition
to
acquire
water‐reinforced
responding
under
the
FR
1
schedule
of
reinforcement.
This
finding
suggests
that
prenatally
cocaine‐exposed
rats
are
more
sensitive
to
reinforcing
effects
of
cocaine
but
not
to
other
reinforcers.
Hecht
et
al.
(1998)
extended
the
work
of
the
previous
groups
to
measure
the
reinforcing
strength
of
cocaine
using
a
progressive‐ratio
(PR)
schedule
of
reinforcement.
Prenatally
cocaine‐exposed
rats
had
significantly
lower
break
points
than
controls
suggesting
that
these
animals
were
less
sensitive
to
the
32
reinforcing
strength
of
cocaine.
However,
Rocha
et
al.
(2002)
reported
conflicting
data
in
mice.
Different
doses
of
cocaine
(0.25‐2.0
mg/kg/injection)
were
made
available
under
an
FR
1
schedule
of
reinforcement
to
examine
vulnerability
to
self‐administer
cocaine.
While
there
were
no
differences
between
prenatally
cocaine‐exposed
and
control
mice
in
acquisition
of
food‐
reinforced
responding
or
to
cocaine
self‐adminstration,
a
greater
number
of
the
prenatally
cocaine‐exposed
mice
reached
the
criteria
for
acquisition
at
all
the
doses
tested
(Rocha
et
al.,
2002).
This
suggests
that
prenatally
cocaine
exposed
subjects
may
be
more
vulnerable
to
cocaine
reinforcement.
NONHUMAN
PRIMATE
MODELS
This
dissertation
work
utilizes
laboratory
animals
and
behavioral
pharmacology
methodology
to
study
the
long‐term
effects
of
prenatal
cocaine
exposure
and
vulnerability
to
self‐administration
of
cocaine.
Human
studies
involving
prenatal
cocaine
exposure
have
resulted
in
inconsistent
findings
that
can
be
attributed
to
difficulties
in
controlling
for
potentially
confounding
variables,
such
as
level
of
pre‐
and
post‐natal
care,
inadequate
nutrition
during
pregnancy,
multiple
drug
use
during
pregnancy,
and
drug
dosage
(Karmel
and
Gardner,
1996;
Richardson
et
al.,
1996;
Gingras
and
O'Donnell,
1998;
Dow‐
Edwards
et
al.,
1999;
Mayes
et
al.,
2003;
Singer
et
al.,
2004);
these
variables
can
be
controlled
in
animal
studies.
Women
who
use
cocaine
while
pregnant
use
greater
amounts
of
other
drugs
(Singer
et
al.,
2000;
2001),
indicating
that
simultaneous
control
for
other
33
prenatal
drug
exposures
is
important
when
evaluating
the
direct
effects
of
cocaine
on
developmental
outcomes
later
in
life.
For
example,
attentional
measures,
which
have
been
examined
in
prenatal
cocaine
studies,
have
been
shown
to
be
vulnerable
to
the
effects
of
prenatal
alcohol
(Fried
et
al.,
1992),
marijuana
(Leech
et
al.,
1999),
and
tobacco
(Fried
et
al.,
1992).
In
addition,
prenatal
tobacco
exposure
has
been
associated
with
conduct
disorder
in
boys
(Wakschlag
and
Hans,
2002)
and
externalizing
behaviors,
anxiety,
and
depression
(Cornelius
et
al.,
2001).
Research
on
fetal
alcohol
exposure
has
also
shown
a
range
of
cognitive
and
behavioral
effects
with
exposed
children
having
more
internalizing
and
externalizing
behavior
problems
(Bailey
et
al.,
2004;
Sood
et
al.,
2001)
and
psychiatric
disorders
(O’Connor
et
al.,
2002).
Further
obfuscating
the
direct
effects
of
prenatal
cocaine
exposure,
caregivers
who
use
drugs
may
expose
their
children
to
chaotic
rearing
environments
and/or
passive
drug
exposure
through
secondhand
tobacco,
marijuana,
or
cocaine
smoke.
The
behavioral
outcome
evaluations
of
children
exposed
to
cocaine
in
utero
have
generated
equivocal
results
regarding
the
domains
affected,
which
highlights
the
need
for
longitudinal
studies
that
control
for
confounding
environmental
and
biologic
factors
such
as
prenatal
exposure
to
other
drugs
and
alcohol.
Therefore,
investigating
the
neurobiological
and
behavioral
consequences
of
prenatal
cocaine
exposure
in
highly
controlled
animal
models
is
an
important
complement
to
the
human
studies.
Nonhuman
primates
(NHP),
especially
rhesus
macaques
(Macaca
mulatta),
offer
numerous
advantages
compared
to
other
animals
for
the
study
of
prenatal
cocaine
exposure.
For
instance,
NHP
are
very
34
similar
to
humans
in
physiology
and
brain
organization
(Goldman‐Rakic
and
Brown,
1982;
Schneider
and
Suomi,
1992;
Silk
et
al.,
1993).
NHP
have
approximately
95%
gene
homology
to
humans
(Hacia
et
al.,
1998)
and
greater
homology
in
DA,
5‐HT,
and
NE
systems
than
rodents
(Weerts
et
al.,
2007).
Additionally,
NHP
have
similar
in
utero
development
as
humans
over
a
long
gestation
period
(24‐26
weeks)
(Silk
et
al.,
1993),
making
them
especially
valuable
for
prenatal
cocaine
exposure
studies.
Another
line
of
evidence
that
NHP
may
be
preferential
compared
to
rodents
for
prenatal
cocaine
exposure
studies
is
that
the
behavioral
and
neurochemical
response
to
psychostimulants
may
be
different
between
the
species.
There
is
evidence
suggesting
species
differences
between
NHP
and
rodents
in
the
metabolic
effects
of
cocaine
(Lyons
et
al.,
1996),
the
behavioral
effects
of
psychostimulants
(Roberts
et
al.,
1999;
Lile
et
al.,
2003),
and
the
DA
receptor
distribution
(Richfield
et
al.,
1987;
Camps
et
al.,
1990).
Finally,
NHP
can
be
utilized
for
longitudinal
studies
due
to
their
relatively
long
lifespan
compared
to
rodents
so
the
long‐term
effects
of
prenatal
cocaine
exposure
can
be
fully
examined.
Therefore,
the
major
strengths
of
the
studies
in
this
dissertation
are
that
NHP
models
are
more
analogous
to
the
human
condition
than
any
other
animal
model,
that
NHP
allow
for
the
study
of
long‐term
effects
in
adults
(beginning
13
years
after
gestational
cocaine
exposure),
that
NHP
have
similar
neurochemical,
hormonal,
and
neuroanatomical
functions,
and
that
NHP
allow
for
the
study
of
multiple
behaviors,
making
these
extremely
translational
studies.
35
PRENATAL
COCAINE
EXPOSURE:
NONHUMAN
PRIMATES
There
have
been
four
research
groups
that
have
examined
the
effects
of
prenatal
cocaine
exposure
in
NHP.
The
majority
of
the
work
with
prenatally
cocaine‐exposed
NHP
has
concentrated
exclusively
on
the
physiological
consequences.
Ronnekleiv
and
colleagues
mainly
focused
on
fetal
brain
development
during
in
utero
cocaine
exposure.
Briefly,
3.0
mg/kg
cocaine
was
administered
i.m.
to
the
mothers
four
times
daily
while
control
subjects
received
saline
injections
four
times
daily.
The
treatment
regimen
began
on
day
18
of
pregnancy
and
continued
until
researchers
removed
the
fetus
at
day
60.
Ronnekleiv
and
Naylor
(1995)
reported
that
TH
messenger
ribonucleic
acid
(mRNA)
content,
as
measured
by
quantitative
in
situ
hybridization,
was
reduced
in
the
substantia
nigra
and
ventral
tegmental
areas
after
60
days
of
prenatal
cocaine
exposure,
which
suggests
reduced
DA
synthesis.
Also,
increases
in
DA
D1,
D2,
and
D5
receptor
subtype
mRNA
levels
in
the
frontal
cortex
and
striatal
areas
were
observed
(Choi
and
Ronnekleiv,
1996).
In
vitro
receptor
autoradiography
later
revealed
signficant
increases
in
D1‐
and
D2‐like
receptor
densities
in
the
striatum
and
substantia
nigra
(Fang
et
al.,
1997)
and
significant
increases
in
DA
transporter
mRNA
and
densities
(Fang
and
Ronnekliev,
1999).
While
Ronnekleiv
and
colleagues
have
not
reported
any
functional
consequences
of
this
prenatal
cocaine
exposure
regimen,
they
have
noted
that
these
alterations
in
DA
neurocircuitry
could
affect
motivation
and
reward
(Fang
et
al.,
1997).
A
second
research
group
has
examined
prenatal
cocaine
exposure
in
NHP
using
a
different
treatment
regimen.
Lidow
and
colleagues
treated
pregnant
36
monkeys
with
10
mg/kg
cocaine
p.o.
twice
a
day
from
E40‐E102
and
allowed
them
to
deliver
the
offspring
at
full‐term.
No
differences
in
weight
of
offspring,
signs
of
atrophy,
or
hemorrhages
were
seen
between
the
prenatally
cocaine
exposed
infants
and
saline‐treated
controls
(Lidow,
1995b).
However,
the
volume
and
weight
of
the
brains
of
the
cocaine‐treated
infants
were
about
20%
lower
compared
to
the
brains
of
the
saline‐treated
infants
(Lidow,
1995b).
Other
studies
from
this
group
have
described
higher
incidence
of
cell
death
in
the
developing
cerebrum
of
cocaine‐exposed
infants
(He
et
al.,
1999)
and
abnormal
neurocortical
cytoarchitecture
(Lidow
and
Song,
2001a,
2001b).
Both
the
Lidow
and
Ronnekleiv
research
groups
have
shown
that
prenatal
cocaine
exposure
has
detrimental
effects
on
the
developing
brain
in
NHP.
A
third
group
that
has
examined
the
effects
of
cocaine
exposure
during
gestation
used
osmotic
minipumps
to
infuse
cocaine
(0.3
mg/kg/hr)
or
saline
continuously
in
pregnant
rhesus
monkeys
(Howell
et
al.,
2001).
Compared
to
a
pair‐fed
control
group,
signficantly
lower
survival
rates
were
found
for
the
cocaine‐exposed
fetuses
(Howell
et
al.,
2001),
which
is
consistent
with
the
documentation
of
increased
stillbirths,
spontaneous
abortions,
and
in
utero
death
from
human
studies
(Chasnoff
et
al.,
1985;
Bingol
et
al.,
1987;
Lutiger
et
al.,
1991).
Of
the
monkeys
that
survived
to
full‐term,
there
were
no
physiological
differences
observed
between
prenatally
cocaine
exposed
and
control
subjects,
including
body
weight,
body
length,
and
heart
rate
(Howell
et
al.,
2001).
None
of
these
studies
in
NHP
have
investigated
the
long‐term
consequences
of
the
gestational
cocaine
exposure.
The
monkeys
used
in
the
37
experiments
included
in
this
dissertation
are
the
first
prenatally
cocaine
exposed
NHP
to
be
examined
for
biological
or
behavioral
effects
beyond
infancy.
The
twenty
monkeys
used
in
these
dissertation
studies
have
been
part
of
research
by
Paule
and
colleagues
since
inception
(for
descriptions
see
Morris
et
al.,
1996,
1997).
Female
rhesus
monkeys
were
administered
1.0
mg/kg
cocaine
i.m.
three
times
a
day,
five
days
a
week.
This
dosing
began
prior
to
mating.
The
dose
of
cocaine
was
increased
weekly
so
that
by
the
end
of
gestation,
the
pregnant
monkeys
were
receiving
between
4.5‐8.5
mg/kg/injection
cocaine
three
times
per
day.
The
mean
cumulative
intake
of
monkeys
in
this
group
was
1131.5
mg/kg
(Table
1).
The
dose
and
frequency
of
cocaine
over
the
pregnancy
was
carefully
controlled
and
rigorous
controls
for
factors
such
as
nutritional
status
of
the
mothers,
stress
from
drug
injections,
and
postnatal
rearing
were
in
place
increasing
the
likelihood
that
prenatal
cocaine
was
the
primary
independent
variable
influencing
long‐term
behavioral
assessments.
Compared
to
controls,
no
differences
were
observed
in
the
maternal
characteristics
of
body
weight,
food
intake,
and
length
of
pregnancy.
However,
decreased
infant
body
weight,
body
length,
and
crown
circumference
were
noted
in
the
prenatally
cocaine
exposed
monkeys
at
birth
compared
to
controls
(Morris
et
al.,
1997).
No
differences
were
observed
between
groups
though
with
respect
to
postnatal
growth
of
the
offspring
over
the
first
18
months
(Morris
et
al.,
1996)
and
the
mean
weight
of
the
two
groups
has
not
been
significantly
different
since
12
months
of
age.
38
Morris
and
colleagues
investigated
the
behavioral
consequences
of
prenatal
cocaine
exposure
using
an
Operant
Test
Battery
(OTB),
which
has
been
described
in
detail
(Morris
et
al.,
1996).
The
OTB
consists
of
five
components:
1)
motivation
as
assessed
by
PR
responding
maintained
by
banana‐flavored
food
pellets;
2)
color
and
position
discrimination;
3)
short‐term
memory
using
a
delayed
matching‐to‐sample
task;
4)
timing
behavior
which
was
assessed
with
a
temporal
response
differentiation
task;
and
5)
learning
using
a
repeated
acquisition
task
(Paule
et
al,
2000).
No
differences
in
the
acquisition
of
any
of
the
five
behavioral
components
were
observed
between
the
prenatally
cocaine
exposed
monkeys
and
controls
(Morris
et
al.,
1996).
In
fact,
the
only
behavioral
difference
Paule
and
colleagues
ever
documented
between
the
two
groups
was
that
the
prenatally
cocaine
exposed
monkeys
perseverated
on
the
simple
visual
discrimination
task
longer
than
control
monkeys
when
the
stimuli
on
this
task
were
reversed
after
six
years
of
performing
the
task
(Chelonis
et
al.,
2003).
This
deficit
in
task
performance
was
still
apparent
2.5
years
after
the
rule
reversal
indicating
that
prenatal
cocaine
exposure
may
permanently
impair
the
ability
of
the
subjects
to
respond
to
environmental
changes
(Chelonis
et
al.,
2003).
The
monkeys
from
Paule
and
colleagues’
laboratory
came
to
Wake
Forest
University
in
2006
around
the
age
of
12
years
old
and
began
testing
in
the
experiments
described
in
this
dissertation
at
this
point.
From
the
time
they
began
testing,
there
were
no
differences
in
weight
between
the
two
groups
(Table
1).
39
TABLE
1.
SUBJECT
DEMOGRAPHICS
CONTROLS
ID
Sex
1553
F
1556
F
1558
F
1559
F
1561
F
1564
M
1566
M
1661
M
1662
M
1663
M
Mean
(±
SEM)
PRENATALLY
COCAINE
EXPOSED
Weight
(kg)
In
utero
ID
Sex
Cocaine
(mg/kg)
5.9
0.0
1554
F
6.3
0.0
1555
F
7.3
0.0
1557
F
6.0
0.0
1560
F
5.6
0.0
1563
M
7.6
0.0
1565
M
8.4
0.0
1567
M
9.0
0.0
1568
M
7.2
0.0
1569
M
8.2
0.0
1570
M
7.15
0.0
Mean
(±
0.37)
(±
0.00)
(±
SEM)
Weight
(kg)
In
utero
Cocaine
(mg/kg)
6.1
982.5
5.0
912.0
6.4
1248.0
6.0
1132.5
8.2
1084.5
8.7
1138.5
7.5
1404.0
8.1
885.0
7.3
1147.5
8.5
1380.0
7.18
1131.45
(±
0.39)
(±
56.10)
Approximately
half
of
the
subjects
in
each
group
(prenatally
cocaine
exposed
and
controls)
are
female
monkeys.
It
is
known
that
hormonal
changes
across
the
menstrual
cycle
may
have
a
large
effect
on
stimulant
drugs,
particularly
cocaine.
A
consistent
and
greater
mood‐altering
effect
of
stimulant
use
during
the
follicular
phase
of
the
menstrual
cycle
has
been
observed
(for
review,
see
Terner
and
de
Wit,
2006)
and
it
is
thought
that
progesterone
level
fluctuations
may
account,
in
part,
for
this
menstrual
phase
difference
(Evans
and
Foltin,
2006;
Evans,
2007).
Evans
et
al.
(2002)
found
that
cocaine
effects
on
heart
rate
and
ratings
of
“good
drug
effect”
were
increased
more
in
the
follicular
phase
than
in
the
luteal
phase,
demonstrating
that
cocaine’s
effects
can
vary
as
a
function
of
menstrual
cycle
phase.
Additionally,
Czoty
et
al.
(2009)
found
that
D2
40
–like
receptor
availability
varied
across
the
menstrual
cycle
in
macaques
with
D2‐like
receptor
availability
in
the
striatum
being
lower
in
the
follicular
phase
than
in
the
luteal
phase.
Therefore,
specific
considerations
were
taken
into
account
and
the
experiments
in
this
dissertation
were
designed
to
examine
the
dopaminergic
system
(Chapter
II)
and
acquisition
of
cocaine
self‐administration
(Chapter
IV)
in
female
subjects
in
the
follicular
phase
of
the
menstrual
cycle.
IMPULSIVITY
Animal
studies
and
human
magnetic
resonance
imaging
(MRI)
have
documented
specific
regions
(caudate
nucleus,
corpus
callosum,
prefrontal
and
posterior
cortices)
(Avants
et
al.,
2007;
Rao
et
al.,
2007;
Singer
et
al.,
2006)
and
mechanisms
(Buxhoeveden
et
al.,
2006;
Lee
et
al.,
2008;
Morrow
et
al.,
2005;
Ren
et
al.,
2004)
of
brain
damage
related
to
fetal
cocaine
exposure.
These
data,
combined
with
early
patterns
of
cognitive
deficits
and
behavioral
problems
in
humans,
indicate
that
prenatal
cocaine
exposure
exerts
specific
teratologic
effects
on
human
development
during
early
childhood
years
through
its
effect
on
areas
of
the
brain
related
to
higher
order
thinking,
impulse
control,
and
sensation
or
pleasure
seeking.
It
has
been
hypothesized
that
some
negative
effects
of
cocaine,
particularly
those
governed
by
monoamine
rich
areas
of
the
brain
such
as
emotional
regulation
and
impulse
control
(Bandstra
et
al.,
2007),
will
ultimately
lead
to
higher
rates
of
substance
dependence.
It
is
possible
that
the
early
deficits
in
41
attention
and
executive
function
seen
in
the
human
cohort
studies
at
ages
4,
6,
and
9
years
old
may
be
associated
with
disturbances
in
inhibitory
control
in
adolescence
and
adulthood.
Reduced
impulse
control
could
indicate
that
prenatal
exposure
to
cocaine
may
predispose
adolescents
to
greater
drug
use
experimentation
and
a
trajectory
toward
substance
dependence.
High
impulsivity
has
been
strongly
associated
with
drug
addiction
(Jentsch
and
Taylor,
1999;
Bickel
and
Marsch,
2001;
de
Wit
and
Richards,
2004).
However,
the
cause
and
effect
relationships
between
impulsivity
and
substance
abuse
have
been
challenging
to
determine.
Prospective
studies
in
both
humans
and
animals
indicate
that
preexisting
impulsive
traits
may
predispose
individuals
to
drug
use
(Tarter
et
al.,
2003;
Perry
et
al.,
2005,
2008;
Dalley
et
al.,
2007;
Diergaarde
et
al.,
2008;
Marusich
and
Bardo,
2009).
However,
other
studies
in
animals
have
found
that
chronic
stimulant
use
may
cause
deficits
in
impulse
control
(Simon
et
al.,
2007;
Stanis
et
al.,
2008;
Dandy
and
Gatch,
2009).
Some
of
the
difficulty
in
evaluating
impulsivity
is
due
to
it
being
conceptualized
as
a
broad
spectrum
of
behaviors
rather
than
a
single
trait.
Due
to
the
multidimensional
aspect
of
impulsivity,
it
has
been
difficult
to
classify
in
the
scientific
literature
although
a
common
definition
is
‘a
predisposition
toward
rapid,
unplanned
reactions
to
internal
or
external
stimuli
with
diminished
regard
to
the
negative
consequences
of
these
reactions
to
the
impulsive
individual
or
to
others’
(Moeller
et
al.,
2001;
Chamberlain
and
Sahakian,
2007).
Although
it
is
well
accepted
that
42
impulsivity
is
not
a
unitary
construct
but
rather
a
spectrum
of
behaviors,
there
is
not
much
agreement
on
how
to
measure
impulsivity
in
animal
models.
In
human
studies,
impulsivity
is
typically
assessed
by
questionnaires.
Several
distinct
measures
have
been
developed
to
assess
impulsivity
in
animals,
including
1)
choosing
an
immediate,
low
magnitude
reward
over
a
delayed,
large
magnitude
reward,
2)
lack
of
behavioral
inhibition,
and
3)
exaggerated
response
to
novelty.
These
measures
are
the
focus
of
studies
in
Chapter
III.
Impulsive
choice
is
most
commonly
assessed
in
human
studies
using
a
delay
discounting
task
in
which
subjects
are
surveyed
and
asked
to
choose
between
a
small,
immediate
reinforcer
and
a
larger,
delayed
reinforcer.
The
subjective
value
of
the
larger
reinforcer
is
decreased
(e.g.
discounted)
as
the
length
of
time
the
subject
must
wait
to
receive
it
increases.
By
using
a
series
of
choices
between
varying
delay
values,
the
indifference
point
can
be
calculated
as
the
delay
value
at
which
the
smaller,
immediate
reinforcer
is
chosen
as
often
as
the
larger,
delayed
reinforcer.
Delay
discounting
has
been
adapted
for
animal
studies
by
presenting
delay
discounting
choices
as
differing
reinforcement
schedules.
Animals
are
trained
to
make
an
operant
response
on
one
manipulandum
to
obtain
a
small
magnitude
reinforcer
and
to
respond
on
another
manipulandum
to
obtain
a
larger
magnitude
reinforcer
after
a
set
delay.
It
has
been
shown
that
drug
users
discount
the
value
of
both
real
and
hypothetical
delayed
reinforcers
moreso
than
nonusers
(Madden
et
al.,
1997;
Bickel
et
al.,
1999;
Kirby
et
al.,
43
1999;
Coffey
et
al.,
2003),
which
indicates
a
possible
relationship
between
impulsive
choice
and
drug
abuse.
Demonstrating
the
utility
of
delay
discounting
procedures
in
assessing
the
relationship
between
impulsive
choice
and
drug
abuse,
Perry
et
al.
(2005)
used
delay
discounting
measures
in
rats
to
show
that
impulsiveness
was
directly
related
to
vulnerability
to
acquire
cocaine
self‐administration.
Rats
were
divided
into
high
and
low
impulsive
choice
groups
based
on
their
percentage
of
responses
on
the
lever
associated
with
the
larger,
delayed
reinforcer.
When
cocaine
acquisition
was
examined,
the
high
impulsiveness
rats
acquired
self‐administration
more
rapidly
and
at
higher
levels
than
the
low
impulsiveness
rats.
Delay
discounting
studies
have
been
extended
to
nonhuman
primates
(Newman
et
al.,
2008;
Woolverton
et
al.,
2007;
Woolverton
and
Anderson,
2006;
Anderson
and
Woolverton,
2003).
Woolverton
et
al.
(2007)
demonstrated
that
rhesus
monkeys
self‐administering
cocaine
intravenously
show
similar
discounting
rates
comparable
to
humans,
suggesting
they
may
be
an
ideal
model
to
study
the
long‐term
effects
of
drug
abuse
on
impulsivity.
The
studies
in
Chapter
III
are
the
first
to
use
NHP
in
food‐reinforced
delay
discounting
studies.
Response
perseveration
is
the
tendency
to
continue
responding
for
a
reinforcer
despite
the
responses
currently
being
either
unrewarded
or
punished
(McCleary,
1966).
Response
perseveration
tasks
first
establish
a
dominant
response
set
for
an
initial
high
rate
of
reward
that
subjects
then
44
have
to
alter
as
the
response
set
becomes
unrewarded
or
punished
more
than
it
is
rewarded
(Matthys
et
al.,
2004).
It
is
thought
that
increased
response
perseveration
is
a
measure
of
behavioral
inhibition
because
in
these
tasks
subjects
must
stop
their
ongoing
behavior
(Matthys
et
al.,
1998).
Increased
behavioral
inhibition,
as
assessed
by
response
perseveration
tasks,
has
been
shown
in
studies
with
patients
with
externalizing
disorders
where
impulsivity
is
often
a
symptom.
In
nonhuman
primates,
perseverative
responding
can
be
assessed
in
a
variety
of
ways.
One
of
the
simplest
measures
is
to
examine
continued
responding
during
extinguishing
of
food‐
reinforced
behavior
on
a
simple
FR
schedule.
A
subject
that
takes
many
sessions
to
extinguish
responding
(unrewarded
responding)
would
be
considered
more
impulsive
than
a
subject
that
takes
only
a
few
sessions
to
extinguish
responding,
as
described
in
Chapter
III.
Differential
behavioral
response
to
novel
stimuli
has
been
attributed
to
impulsivity
(Goldber,
1990;
Zuckerman,
1996).
In
rodents,
a
strong
correlation
between
novelty
preference
and
impulsive
reactivity
with
both
self‐administration
rates
and
rewarding
efficacy
of
psychomotor
stimulants
has
been
observed
(Hooks
et
al.,
1991;
Abreu‐Villaça
et
al.,
2006;
Davis
et
al.,
2008).
Measuring
impulsivity
by
exposing
subjects
to
a
novel
object
has
also
been
used
successfully
in
nonhuman
primate
studies
(Bolig
et
al.,
1992;
reviewed
in
Clark
and
Boinski,
1995;
Coleman
et
al.,
2005).
Responsiveness
in
an
open
field
is
another
method
commonly
used
to
assess
impulsivity.
Piazza
and
colleagues
demonstrated
that
responsiveness
in
an
open
field
was
45
associated
with
vulnerability
to
stimulant
self‐administration
(Piazza
et
al.,
1989;
1990;
reviewed
in
Piazza
and
Le
Moal,
1998).
It
has
been
proposed
that
locomotor
response
to
a
novel
field
is
closely
related
to
behavioral
disinhibition
(Stoffel
and
Cunningham,
2008).
Humans
have
also
been
shown
to
display
differences
in
reactivity
levels
when
exposed
to
a
novel
environment
(Alessi
et
al.,
1999).
In
Chapter
III,
the
effect
of
prenatal
cocaine
exposure
on
multiple
measures
of
impulsivity,
including
both
unconditioned
and
conditioned
behaviors,
will
be
discussed.
ACQUISITION
OF
COCAINE
SELF­ADMINISTRATION
Although
a
number
of
prospective,
longitudinal
studies
are
currently
investigating
the
role
of
cocaine
in
contributing
to
adverse
outcomes
in
prenatally
exposed
children,
the
impact
of
prenatal
cocaine
exposure
regarding
vulnerability
for
addiction
has
not
been
systematically
examined.
Children
who
were
born
during
the
crack
cocaine
epidemic
of
the
mid‐1980s
and
early
1990s
are
now
entering
young
adulthood,
a
time
when
experimentation
with
drugs
of
abuse
typically
occurs.
Given
the
apparent
links
between
prenatal
cocaine
exposure
and
long‐term
behavioral
and
neural
outcomes
that
are
ostensibly
involved
in
determining
sensitivity
to
cocaine,
it
is
reasonable
to
examine
the
possible
relationship
between
cocaine
exposure
during
gestation
and
the
acquisition
of
cocaine
self‐administration.
It
is
impossible
to
ethically
study
acquisition
of
drug
taking
behavior
in
cocaine‐naïve
humans.
Therefore,
animal
46
models
are
extremely
valuable
in
allowing
researchers
to
examine
variables,
like
prenatal
cocaine
exposure,
that
may
enhance
or
impede
the
initiation
of
drug‐
taking
and
predict
vulnerability
for
drug
abuse.
Acquisition
studies
have
primarily
been
conducted
in
rodents,
due
to
the
prohibitive
expense
of
between‐subject
designs
using
NHP.
However,
there
have
been
a
few
studies
examining
drug
history
variables
in
acquisition
of
self‐administration
of
a
second
drug
in
monkeys
(Pickens
et
al.,
1973;
Young
and
Woods,
1981;
Carroll
et
al.,
1984;
Beardsley
et
al.,
1990;
Nader
and
Mach,
1996;
Wojnicki
and
Glowa,
1996;
Lile
et
al.,
2000).
For
example,
acquisition
of
the
selective
dopamine
reuptake
inhibitor
GBR
12909
self‐
administration
was
studied
in
different
groups
of
rhesus
monkeys
that
were
either
experimentally
naïve
or
had
a
history
of
cocaine
self‐administration.
It
was
determined
that
self‐administration
was
maintained
under
a
multiple
FR30
schedule
with
alternating
components
of
either
food
or
drug
presentation
only
in
the
monkeys
with
previous
cocaine
self‐administration
history
(Wojnicki
and
Glowa,
1996).
However,
experimentally
naïve
monkeys
failed
to
acquire
GBR
12909
self‐adminstration
at
low
doses
(Wojnicki
and
Glowa,
1996).
Similarly,
Beardsley
et
al.
(1990)
demonstrated
that
MK‐801,
the
N‐methyl‐D‐aspartate
(NMDA)
receptor
antagonist,
was
self‐administered
by
rhesus
monkeys
previously
trained
to
self‐administer
phencyclidine
(PCP),
a
different
NMDA
receptor
antagonist,
but
was
not
self‐
administered
by
rhesus
monkeys
previously
trained
to
self‐administer
cocaine.
This
finding
supports
the
general
conclusion
that
prior
exposure
to
a
47
drug
with
similar
pharmacological
actions
facilitates
acquisition
of
self‐
adminstration
in
NHP.
These
studies
also
imply
that
in
utero
cocaine
exposure,
acting
as
a
prior
exposure,
may
increase
vulnerability
to
self‐
administer
cocaine
later
in
life.
In
rodent
studies,
many
types
of
variables
have
been
identified
as
affecting
rate
of
acquisition
of
drug
self‐adminstration.
Like
in
NHP,
drug
history
is
an
important
variable.
Pretreatment
with
amphetamine
(Piazza
et
al.,
1989;
1990),
cocaine
(Horger
et
al.,
1990;
Childs
et
al.,
2006),
naltrexone
(Carroll
et
al.,
1986),
and
caffeine
(Horger
et
al.,
1991)
can
enhance
acquisition
of
psychomotor
stimulant
self‐administration.
Environmental
conditions
such
as
restricted
access
to
food
(DeVry
et
al.,
1989)
and
a
history
of
restricted
feeding
(Specker
et
al.,
1994),
physical
stress
(Shaham
et
al.,
1992;
Goeders
and
Guerin,
1994),
or
social
stress
(Haney
et
al.,
1995)
have
all
been
shown
to
enhance
acquisition
of
drug
taking
in
rats.
Additionally,
characteristics
of
the
animals
have
been
noted
as
predictive
of
faster
acquisition
of
stimulant
self‐administration.
For
example,
high
rate
of
novelty‐induced
locomotor
activity
(Piazza
et
al.,
1989),
preference
of
sweets
(Gosnell
et
al.,
1995),
and
increased
impulsivity
as
assessed
by
a
delay‐of‐
reward
paradigm
(Poulos
et
al.,
1995,
Perry
et
al.,
2005)
have
all
been
determined
to
predict
acquisition
of
self‐administration
of
stimulants.
While
acquisition
studies
typically
hold
the
dose
of
the
drug
constant
at
low
or
moderate
levels
and
manipulate
other
variables,
another
method
of
examining
acquisition
is
to
test
multiple
doses
of
the
drug
and
use
rate
of
48
acquisition
or
probability
of
acquisition
at
various
doses
as
the
dependent
measure
(van
Ree
et
al.,
1978;
Gerrits
and
van
Ree,
1995;
Carroll
and
Lac,
1997;
Zhao
and
Becker,
2009).
The
focus
of
Chapter
IV
was
to
determine
if
prenatal
cocaine
exposure
would
facilitate
rate
of
acquisition
of
self‐administration
of
cocaine
in
adulthood.
Since
it
has
been
argued
that
the
rate
of
acquisition
of
drug
self‐administration
may
serve
as
a
predictor
of
later
drug‐taking
behavior,
possibly
influencing
the
transition
from
drug
use
to
addition
(Rocha
et
al.,
2002;
2005),
the
studies
in
Chapter
IV
were
designed
to
test
acquisition
by
examine
multiple
doses
of
cocaine
and
focusing
on
rate
of
acquisition.
Importantly,
two
factors
that
are
thought
to
predict
vulnerability
to
self‐administration
drugs
of
abuse,
basal
dopaminergic
function
(Chapter
II)
and
impulsivity
(Chapter
III),
were
also
examined.
49
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by
ketamine
and
related
compounds
in
rhesus
monkeys
with
different
self‐
administration
histories.
J
Pharmacol
Exp
Ther
218:
720‐727.
Zhao
W,
Becker
JB
(2009)
Sensitization
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acquisition
of
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self‐
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in
female
rats:
estradiol
further
enhances
cocaine
intake
after
acquisition.
Horm
and
Behav
doi:10.1016/j.yhbeh.2009.09.005.
Zuckerman
B,
Frank
DA,
Hingson
R,
Amaro
H
et
al
(1989)
Effects
of
maternal
marijuana
and
cocaine
use
on
fetal
growth.
N
Eng
J
Med
320:762‐768.
Zuckerman
M
(1996)
The
psychobiological
model
for
impulsive
unsocialized
sensation‐seeking:
a
comparative
approach.
Neuropsychobiology
34:125‐129.
85
CHAPTER
II
CHARACTERIZATION
OF
THE
DOPAMINE
RECEPTOR
SYSTEM
IN
ADULT
RHESUS
MONKEYS
EXPOSED
TO
COCAINE
THROUGHOUT
GESTATION
Lindsey
R.
Hamilton,
Paul
W.
Czoty,
H.
Donald
Gage,
Michael
A.
Nader
The
following
manuscript
was
accepted
for
publication
by
Psychopharmacology
March
2010.
Stylistic
variations
are
due
to
the
requirements
of
the
journal.
Lindsey
R.
Hamilton
performed
the
experiments,
analyzed
the
data,
and
prepared
the
manuscript.
H.
Donald
Gage
aided
in
the
analysis
of
the
positron
emission
tomography
data.
Paul
W.
Czoty
and
Michael
A.
Nader
acted
in
an
advisory
and
editorial
capacity.
86
ABSTRACT
RATIONALE:
Cocaine
use
during
pregnancy
is
associated
with
alterations
in
the
dopamine
(DA)
system
in
the
fetal
brain.
However,
little
is
known
about
the
effects
of
prenatal
cocaine
exposure
on
the
postnatal
dopaminergic
system.
OBJECTIVES:
The
objective
of
the
study
was
to
examine
DA
receptor
function
in
adult
monkeys
that
were
prenatally
exposed
to
cocaine.
MATERIALS
AND
METHODS:
Male
and
female
rhesus
monkeys
(approximately
13
years
old)
that
had
been
prenatally
exposed
to
cocaine
(n
=
10)
and
controls
(n
=
10)
were
used
in
all
studies.
First,
DA
D2‐like
receptor
availability
was
assessed
using
positron
emission
tomography
and
the
D2‐like
receptor
radiotracer
[18F]fluoroclebopride
(FCP).
Next,
D3
receptor
function
was
assessed
by
measuring
quinpirole‐induced
yawning
(0.03‐0.3
mg/kg).
Finally,
D1‐like
receptor
function
was
examined
by
measuring
eye
blinking
elicited
by
the
high‐efficacy
D1‐like
receptor
agonist
SKF
81297
(0.3‐3.0
mg/kg).
RESULTS:
There
were
no
differences
between
groups
or
sexes
in
D2‐like
receptor
availability
in
the
caudate
nucleus,
putamen
or
amygdala.
However,
quinpirole
elicited
significantly
more
yawns
in
prenatally
cocaine‐exposed
monkeys
compared
with
control
monkeys.
A
significant
correlation
between
gestational
dose
of
cocaine
and
peak
effects
of
quinpirole
was
observed.
In
all
monkeys,
administration
of
SKF
81297
elicited
dose‐dependent
increases
in
eye
blinks
that
did
not
differ
between
groups.
CONCLUSIONS:
These
findings
suggest
that
prenatal
cocaine
exposure
can
have
long‐term
effects
on
DA
D3
receptor
function
in
adults.
KEYWORDS:
Prenatal
cocaine
­
D2
receptors
­
PET
imaging
­
Quinpirole
–
SKF
81297
­
Rhesus
monkey
87
It
has
been
estimated
that
over
45,000
infants
born
each
year
have
been
prenatally
exposed
to
cocaine
(National
Pregnancy
and
Health
Survey
1996).
Cocaine
use
during
pregnancy
is
associated
with
several
physical
deficits
including
reduced
body
weight,
body
length,
and
head
circumference
at
birth
(Nair
and
Watson
1991).
However,
the
effects
of
cocaine
use
during
pregnancy
on
postnatal
development
and
long‐term
neurobiological
and
behavioral
outcomes
have
been
less
thoroughly
investigated.
The
present
study
compared
a
population
of
rhesus
monkeys
that
were
prenatally
exposed
to
cocaine
throughout
gestation
to
control
monkeys
with
nearly
identical
pharmacological
and
experimental
histories
(Morris
et
al.
1996,
1997).
At
the
start
of
the
present
study,
these
monkeys
were
adults
(13
years
old),
with
minimal
drug
exposure
since
birth
(see
Paule
et
al.
1996,
2000;
Morris
et
al.
1996).
Despite
the
escalating
cocaine
intakes
of
the
mothers
and
the
lower
infant
weights
at
birth
(Morris
et
al.
1997),
over
the
first
18
months,
no
differences
were
observed
between
cocaine
and
control
groups
with
respect
to
postnatal
growth
(Morris
et
al.
1996).
A
particular
advantage
of
using
nonhuman
primates
in
prenatal
cocaine
exposure
studies
is
the
relatively
long
gestational
period.
In
rhesus
macaques,
the
average
gestational
period
is
approximately
24
weeks
(Silk
et
al.
1993).
Despite
this
advantage,
there
are
no
studies
involving
prenatal
cocaine
exposure
in
rhesus
monkeys
that
have
examined
the
consequences
of
gestational
drug
exposure
in
adults.
88
For
the
present
studies,
the
dopamine
(DA)
neurotransmitter
system
was
examined
using
several
in
vivo
measures.
Within
the
DA
system,
there
are
two
superfamilies
of
DA
receptors,
the
D1‐like
receptors
with
two
receptor
subtypes
D1
and
D5
and
D2‐like
receptors
with
D2,
D3
and
D4
receptor
subtypes.
Both
D1‐
and
D2‐like
receptors
have
been
shown
to
be
affected
by
chronic
cocaine
exposure
in
adult
humans
and
nonhuman
primates
(e.g.,
Moore
et
al.
1998a,
1998b;
Martinez
et
al.
2004;
Nader
et
al.
2002;
Volkow
et
al.
1999).
As
it
relates
to
effects
on
the
fetus,
elevation
of
extracellular
monoamine
concentrations
during
development
may
lead
to
alterations
in
receptor
signaling
mechanisms
at
birth
and
perhaps
throughout
life.
Since
DA
is
among
the
first
neurochemical
pathways
to
develop
in
the
fetal
brain
(reviewed
in
Bhide
2009),
the
long‐lasting
effects
of
cocaine
exposure
on
the
dopaminergic
system
during
this
crucial
development
stage
are
of
particular
interest.
In
the
present
study,
DA
D2‐like
receptor
availability
was
assessed
using
positron
emission
tomography
(PET)
and
the
tracer
[18F]fluoroclebopride
(FCP),
which
does
not
differentiate
between
D2‐like
receptor
subtypes
(Mach
et
al.
1996).
In
adult
rhesus
monkeys,
D2‐like
receptor
availability
has
been
shown
to
decrease
as
a
consequence
of
chronic
cocaine
exposure
(Nader
et
al.
2006).
We
hypothesized
that
D2‐like
receptor
availability
would
be
lower
in
adult
monkeys
who
had
been
exposed
to
cocaine
throughout
gestation.
While
data
suggest
that
D2‐like
receptors
are
reduced
due
to
cocaine
exposure,
post‐mortem
studies
found
D3
receptors
to
89
be
higher
in
cocaine
overdose
victims
compared
to
age‐matched
controls
(Staley
and
Mash
1996).
Thus,
we
used
the
D3/D2
agonist
quinpirole
and
the
unconditioned
behavior
yawning
to
assess
D3
receptor
function
in
vivo.
Earlier
work
in
rodents
has
shown
that
the
ascending
limb
of
the
quinpirole‐
elicited
yawning
dose‐response
curve,
including
the
peak
of
the
curve,
is
mediated
by
D3
receptors
(Collins
et
al.
2005).
As
it
relates
to
D1
receptors,
Jones
et
al.
(2000)
demonstrated
that
prenatal
cocaine
exposure
induced
early
desensitization
of
DA
D1‐like
receptors
in
fetal
rabbit
anterior
cingulate
cortex
and
caudate
nucleus
that
occurred
without
alterations
of
the
receptor
protein
itself,
suggesting
that
the
D1‐like
receptors
become
uncoupled
from
their
G‐protein
(Lidow
1998;
Jones
et
al.
2000).
Importantly,
D1‐like
receptor
alterations
in
rabbits
and
rodents
prenatally
exposed
to
cocaine
have
been
shown
to
persist
into
adolescence
and
adulthood
(Bayer
et
al.
2000;
Stanwood
and
Levitt
2007).
Therefore,
in
the
present
study,
D1‐like
receptor
function
was
investigated
by
assessing
the
ability
of
the
high‐efficacy
agonist
SKF
81297
to
elicit
eye
blinking
(Jutkiewicz
and
Bergman
2004).
For
these
studies,
there
was
a
near
equal
distribution
of
male
and
female
monkeys,
so
the
effects
of
prenatal
cocaine
exposure
and
sex
were
factors
in
all
analyses.
MATERIALS
AND
METHODS
SUBJECTS. Twenty
adult
rhesus
monkeys
(Macaca
mulatta),
born
between
1993
and
1995
and
raised
at
the
FDA
facility
in
Little
Rock,
AR
until
their
90
arrival
at
Wake
Forest
University
in
2007,
served
as
subjects.
Ten
monkeys
(6
male,
4
female)
were
prenatally
exposed
to
cocaine
and
10
monkeys
(5
male,
5
female)
were
controls,
as
described
previously
(Morris
et
al.
1996,
1997).
Briefly,
mothers
of
cocaine‐exposed
monkeys
received
intramuscular
injections
of
escalating
doses
of
cocaine
three
times
per
day
for
the
entire
course
of
gestation;
the
mean
cumulative
cocaine
intake
was
1131.5
(±
56.1
SEM)
mg/kg
(Morris
et
al.
1996).
At
6
months
of
age,
all
monkeys
were
housed
individually
in
the
same
colony
room
and
began
behavioral
training
involving
an
operant
test
battery
(Morris
et
al.
1997).
Other
than
their
prenatal
drug
histories,
all
monkeys
had
identical
experimental
histories,
including
acute
exposure
to
cocaine,
amphetamine,
haloperidol,
quinpirole,
SCH‐23390,
spiperone,
and
MK‐801
(see
Paule
et
al.
1996;
Morris
et
al.
1997;
personal
communication
from
M.
Paule).
At
the
time
of
the
present
studies,
there
were
no
significant
differences
between
the
prenatally
cocaine
exposed
and
control
monkeys
in
age
(12.4
±
0.3
years
vs.
12.9
±
0.3
years,
respectively)
or
weight
(7.8
±
0.7
kg
vs.
6.4
±
0.4
kg,
respectively).
Monkeys
were
individually
housed
in
stainless‐steel
cages
with
water
available
ad
libitum
and
had
visual
and
auditory
contact
with
each
other.
During
a
2‐month
quarantine,
a
free‐feeding
weight
was
determined
and
monkeys’
body
weights
were
maintained
at
approximately
95%
of
that
value
throughout
these
studies
(LabDiet
Monkey
Chow
and
fresh
fruit).
Each
monkey
was
fitted
with
an
aluminum
collar
(Primate
Products,
Redwood
City,
CA)
and
trained
to
sit
calmly
in
a
standard
primate
chair
(Primate
91
Products)
using
a
specially
designed
stainless‐steel
pole
that
attached
to
the
collar.
All
experimental
and
environmental
enrichment
protocols
were
approved
by
the
Wake
Forest
University
Institutional
Animal
Care
and
Use
Committee.
The
experiments
are
listed
in
the
order
that
each
animal
was
tested.
MENSTRUAL
PHASE
DETERMINATION. Since
we
have
previously
shown
that
D2
receptor
availability
differs
across
the
menstrual
cycle
(Czoty
et
al.
2009),
all
experiments
were
conducted
in
the
follicular
phase.
Menstrual
cycle
was
assessed
by
daily
vaginal
swabs.
Days
of
bleeding
were
recorded
as
indicative
of
menses.
PET
scans
were
scheduled
to
occur
during
the
follicular
phase
(days
2‐12).
To
confirm
cycle
phase,
on
the
day
of
a
PET
study,
3
ml
of
blood
was
drawn
from
the
femoral
vein
and
analyzed
for
progesterone
at
the
Biomarkers
Core
Laboratory
of
the
Yerkes
National
Primate
Research
Center
of
Emory
University
in
Atlanta,
GA
(see
Czoty
et
al.
2009
for
details).
EXPERIMENT
1:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
D2
RECEPTOR
AVAILABILITY.
Magnetic
resonance
imaging
(MRI)
scans
were
acquired
for
each
monkey.
Twenty
minutes
before
the
MRI,
subjects
were
anesthetized
with
ketamine
(15‐20
mg/kg,
i.m.)
and
transported
to
the
MRI
facility.
Anesthesia
was
maintained
during
the
scanning
procedure
with
ketamine
supplements
when
necessary.
T1‐weighted
images
of
the
entire
brain
were
acquired
with
a
1.5‐Tesla
GE
Signa
NR
scanner
(GE
Medical
92
Systems).
Images
were
used
to
anatomically
define
regions
of
interest
(ROIs),
including
the
caudate
nucleus,
putamen,
amygdala,
and
cerebellum,
for
later
co‐registration
with
PET
images.
PET
data
were
acquired
using
a
GE
Advance
NXi
PET
scanner
(~4.8
mm3
resolution)
and
the
radiotracer
[18F]fluoroclebopride
(FCP),
which
binds
with
high
affinity
to
D2‐like
receptors
(Mach
et
al.
1993)
with
a
test/retest
variability
of
~2%
(Nader
et
al.
1999).
Methodological
details
regarding
the
data
acquisition
protocol,
blood
sampling
and
metabolite
analysis
for
FCP
have
been
described
previously
(Mach
et
al.
1996;
Nader
et
al.
1999).
Approximately
30
min
before
the
scan,
monkeys
were
anesthetized
with
ketamine
(10
mg/kg,
i.m.),
intubated,
and
maintained
throughout
the
scan
by
inhaled
isoflurane
(1.5%).
This
induction
protocol
does
not
alter
D2
receptor
availability
as
measured
with
FCP
(Nader
et
al.
1999).
Catheters
were
placed
in
an
external
artery
and
vein
by
percutaneous
sticks
and
saline
was
delivered
to
the
monkey
throughout
the
scan.
Body
temperature
was
maintained
at
38°C
and
vital
signs
(heart
rate,
blood
pressure,
respiration
rate,
and
temperature)
were
monitored
throughout
the
scanning
procedure.
A
paralytic
(0.07
mg/kg
vecuronium
bromide)
was
administered
i.v.
and
respiration
was
maintained
by
a
ventilator.
Supplemental
doses
of
vecuronium
bromide
(0.1
mg/h)
were
administered
throughout
the
study.
A
5‐min
transmission
scan
was
acquired
in
2D
mode.
Next,
the
monkey
received
a
bolus
dose
of
[18F]FCP
(2‐5
mCi)
followed
by
a
3
ml
flush
with
heparinized
saline
and
a
180
min
dynamic
acquisition
scan
was
93
acquired.
Twenty‐six
frames
were
acquired
over
3
hr
(5
x
1
min,
5
x
2
min,
5
x
5
min,
8
x
10
min,
3
x
20
min)
in
3D
mode
(i.e.,
septa
retracted).
Image
reconstruction
of
3D
data
was
done
using
the
3D‐reprojection
method
(Rogers
et
al.
1987)
with
full
quantitative
corrections.
Once
the
scanning
was
compete,
the
transmission
scan
data
were
smoothed
transaxially
using
a
4‐
mm
Gaussian
filter
and
segmented
(Bettinardi
1999).
Emission
data
were
corrected
for
attenuation
and
reconstructed
into
129
x
128
matrices
using
a
Hanning
filter
with
a
4‐mm
cutoff
transaxially
and
a
ramp
filter
with
an
8.5‐
mm
cutoff
axially.
The
first
five
frames
of
each
study's
PET
image
data
were
then
added
together.
This
summed
image
represents
tracer
uptake
in
the
early
part
of
the
study
and
approximates
a
blood
flow
image.
The
image
was
then
registered
to
the
animal’s
MRI
using
the
AIR
algorithm
(Woods
et
al.
1993)
after
extracting
the
brain
image
from
the
MRI,
using
the
method
of
Smith
(2002).
Time‐activity
curves
were
generated
for
radiotracer
concentrations
in
ROIs
defined
on
each
subject’s
co‐registered
MRI.
Distribution
volume
ratios
(DVR)
were
calculated
for
each
ROI
using
the
cerebellum
as
the
reference
region
and
the
graphical
method
of
Logan
et
al.
(1996).
The
DVR
thus
served
as
an
index
of
specific
FCP
binding
in
each
ROI.
For
all
regions,
the
right
and
left
sides’
DVRs
did
not
differ
and
were
averaged.
EXPERIMENT
2:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
QUINPIROLE­INDUCED
YAWNING.
A
quinpirole
dose‐response
curve
was
94
determined
for
each
monkey.
Before
each
experimental
session,
the
monkey
was
placed
in
a
primate
chair
and
given
an
injection
of
saline
(1.0
ml)
or
quinpirole
(0.03,
0.1,
or
0.3
mg/kg,
i.m.);
doses
were
tested
in
random
order
with
at
least
2
days
between
testing.
These
doses
of
quinpirole
do
not
induce
hypothermia
in
our
monkeys
(unpublished
observations),
an
effect
described
as
D2
receptor‐mediated
effect
observed
in
rodents
(Boulay
et
al.
1999a,
b;
Chaperon
et
al.
2003;
Collins
et
al.
2007).
Immediately
after
the
injection,
occurrences
of
yawning
were
counted
for
30
minutes.
Full
extension
of
the
jaws,
withdrawal
of
the
lips,
and
exposure
of
the
teeth
characterized
yawning
(Code
and
Tang
1991).
Sessions
were
videotaped
and
two
people
who
were
blind
to
the
monkeys’
prenatal
history
scored
these
sessions
with
an
inter‐
observer
variability
of
<5%.
EXPERIMENT
3:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
SKF
81297­INDUCED
EYE
BLINKING.
Monkeys
were
seated
in
a
primate
chair
in
a
testing
room.
Following
a
15
minute
acclimation
period,
saline
(1.0
ml)
was
administered
into
the
saphenous
vein
and
blinking
was
counted
during
the
last
2.5
minutes
of
the
following
15
minute
period.
Subsequently,
cumulative
doses
of
SKF
81297
(0.3,
1.0,
and
3.0
mg/kg,
i.v.)
were
administered
and
blinking
was
counted
in
the
last
2.5
minutes
of
the
15
minute
period
following
each
dose.
Total
session
length
was
75
minutes.
Sessions
were
videotaped
and
two
people,
one
of
whom
was
blind
to
the
monkeys’
prenatal
drug
history,
scored
these
sessions
with
an
inter‐observer
variability
of
<8%.
95
Drugs.
Quinpirole
(Sigma‐Aldrich,
St.
Louis,
MO)
was
dissolved
in
sterile
saline
to
a
concentration
of
1.0
mg/ml.
SKF
81297
(Sigma‐Aldrich,
St.
Louis,
MO)
was
dissolved
in
sterile
saline
to
a
concentration
of
5.0
mg/ml.
All
doses
are
expressed
as
the
salt.
STATISTICAL
ANALYSIS.
In
Experiment
1,
for
each
ROI,
data
were
analyzed
using
a
two‐way
repeated
measures
ANOVA
with
group
(prenatal
cocaine
and
control)
and
sex
as
factors.
In
Experiments
2
and
3,
three‐way
repeated
measures
ANOVAs
with
group,
sex
and
dose
(quinpirole
or
SKF
81297)
as
factors
were
conducted.
In
all
cases,
significance
was
accepted
at
the
95%
level
of
confidence
(p
<
0.05).
RESULTS
EXPERIMENT
1:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
D2
RECEPTOR
AVAILABILITY.
For
all
monkeys,
there
was
a
high
level
of
uptake
of
[18F]FCP
in
all
three
regions
of
interest
and
a
linear
rate
of
washout,
as
shown
previously
(e.g.
Morgan
et
al.
2002).
In
the
cerebellum,
[18F]FCP
uptake
was
low
with
a
rapid
rate
of
washout
(not
shown).
For
both
groups
of
monkeys,
[18F]FCP
DVRs
in
the
caudate
nucleus
and
putamen
were
higher
than
DVRs
observed
in
the
amygdala
in
all
monkeys
(Fig.
1).
There
were
no
96
significant
main
effects
of
prenatal
cocaine
exposure
or
sex
and
no
group
x
sex
interactions
for
any
ROI.
EXPERIMENT
2:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
QUINPIROLE­INDUCED
YAWNING.
Using
a
3‐way
repeated
measures
ANOVA,
there
was
a
significant
effect
of
quinpirole
dose
[F(3,
48)=7.13,
p<0.001],
and
group
[F(1,
16)=8.51,
p<0.01]
and
a
significant
sex
x
quinpirole
dose
interaction
[F(3,
48)=3.42,
p<0.05]
(Fig.
2).
All
quinpirole
doses
elicited
more
yawns
in
the
prenatal
cocaine‐exposed
monkeys
compared
to
controls
(Fig.
2,
right
panel).
Male
monkeys,
irrespective
of
their
prenatal
condition,
yawned
more
following
0.03
mg/kg
quinpirole
compared
to
female
monkeys
whose
quinpirole
curve
peaked
at
0.1
mg/kg
(Fig.
2,
left
and
middle
panels).
For
control
and
prenatally
cocaine‐exposed
monkeys
(male
and
female),
all
quinpirole
doses
elicited
more
yawns
than
saline,
but
the
dose‐response
curves
were
relatively
flat
(Fig.
2,
right
panel).
Finally,
combining
the
data
for
all
prenatally
cocaine‐exposed
monkeys
(Fig.
3)
revealed
a
significant
positive
correlation
between
the
maximal
effect
of
quinpirole
and
maximal
daily
in
utero
cocaine
exposure
(r2
=
0.84,
p
<
0.0005).
However,
when
cumulative
gestational
cocaine
dose
was
used
in
the
analysis,
the
correlation
was
not
signficant.
EXPERIMENT
3:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
SKF
81297­INDUCED
EYE
BLINKING.
Following
saline
administration,
rates
of
97
blinking
ranged
from
4.8‐17.2
blinks
per
minute
but
did
not
differ
between
prenatally
cocaine
exposed
and
control
monkeys
(Fig
4).
A
repeated‐
measures
three‐way
ANOVA
revealed
a
significant
main
effect
of
SKF
81297
dose
[F(3,39)=45.80,
p<0.001]
and
SKF
81297
dose
x
sex
interaction
[F(3,39)=3.11,
p<0.05].
For
both
groups
and
across
all
SKF81297
doses,
males
blinked
more
than
females.
DISCUSSION
The
purpose
of
the
present
studies
was
to
determine
if
there
were
long‐term
alterations
in
dopamine
function
in
adult
monkeys
that
were
exposed
to
cocaine
in
utero.
Ten
monkeys
(male
and
female)
prenatally
exposed
to
cocaine
were
compared
to
10
age‐matched
control
monkeys
who
had
nearly
identical
postnatal
experimental
histories.
There
were
no
differences
between
groups
in
D1‐like
receptor
function,
as
assessed
by
SKF
81297‐elicited
eye
blinks,
or
in
D2‐like
receptor
availability
as
determined
with
PET
imaging.
In
contrast,
the
D3/D2
receptor
agonist
quinpirole
elicited
significantly
more
yawns
in
monkeys
prenatally
exposed
to
cocaine
compared
to
control
monkeys.
Furthermore,
a
significant
correlation
was
observed
between
maximal
daily
gestational
dose
of
cocaine
and
peak
effects
of
quinpirole.
These
findings
suggest
long‐lasting
effects
of
prenatal
cocaine
exposure
on
DA
D3
receptor
function.
Accumulating
evidence
suggests
that
chronic
cocaine
exposure
can
produce
significant
reductions
in
DA
D2‐like
receptor
availability
in
adult
98
humans
and
animals
(e.g.,
Volkow
et
al.
1999;
Martinez
et
al.
2004;
Nader
et
al.
2002,
2006).
However,
earlier
work
suggested
that
the
effects
of
chronic
cocaine
on
fetal
DA
receptor
densities
may
be
different
from
those
observed
in
adults.
For
example,
Fang
et
al.
(1997)
observed
significantly
higher
levels
of
D2‐like
receptor
densities
in
the
fetal
monkey
striatum
following
gestational
cocaine
exposure.
Data
from
the
present
PET
imaging
study
suggest
that
any
changes
in
D2‐like
receptor
availability
that
may
have
occurred
in
utero
or
in
the
developing
brain
have
recovered
in
adulthood.
Compared
to
the
Fang
et
al.
(1997)
rhesus
monkey
study,
the
present
study
involved
longer
in
utero
treatments
(approximately
6
months),
full‐term
pregnancy
and
13
years
of
abstinence.
Future
longitudinal
PET
imaging
experiments
conducted
at
multiple
points
during
a
monkey’s
lifespan
following
in
utero
cocaine
exposure
would
directly
address
the
time
course
of
recovery.
No
significant
sex
differences
were
observed
in
D2‐like
receptor
availability
in
any
of
the
regions
of
interest.
This
is
consistent
with
the
lack
of
sex
differences
seen
in
striatal
D2/D3
receptor
binding
using
[18F]‐fallypride
in
adolescent
rhesus
monkeys
(Christian
et
al.
2009)
and
with
previous
reports
of
women
and
men
showing
equivalent
D2‐like
receptor
availability
(Farde
et
al.
1995;
Pohjalainen
et
al.
1998;
Munro
et
al.
2006).
However,
it
has
been
suggested
that
female
sex
hormones
may
enhance
presynaptic
dopamine
turnover
(Laakso
et
al.
2002)
and
the
radiotracer
used
in
this
experiment
(FCP)
is
sensitive
to
fluctuations
in
menstrual
cycle
phase
(Czoty
99
et
al.
2009).
In
addition,
sex
differences
have
been
reported
in
a
study
using
[11C]raclopride
and
PET
in
healthy
men
and
women
of
ages
ranging
from
19‐
82
yrs
old
(Pohjalainen
et
al.
1998).
Therefore,
it
remains
possible
that
differences
in
D2‐like
receptor
availability
in
males
and
females
may
have
been
observed
at
earlier
time
points
or
may
yet
be
seen
as
these
monkeys
age.
The
PET
radiotracer
used
in
the
present
study
does
not
differentiate
between
D2,
D3
and
D4
subtypes
of
the
D2‐like
receptor
superfamily.
Thus,
it
is
conceivable
that
prenatal
cocaine
exposure
could
have
long‐term
effects
on
subtypes
of
this
superfamily
which
would
be
obscured
by
opposite
adaptations
in
another
subtype.
For
example,
in
vitro
receptor
autoradiography
studies
have
shown
lower
D2‐like
receptor
densities
(e.g.,
Moore
et
al.
1998;
Nader
et
al.
2002)
and
higher
D3
receptor
densities
(e.g.,
Staley
and
Mash
1996)
in
cocaine‐exposed
individuals
compared
to
age‐
matched
controls.
To
determine
if
there
were
differences
in
D3
receptor
function,
the
D3
receptor
agonist
quinpirole
was
used
to
examine
the
sensitivity
of
behavior
related
to
this
subtype
in
both
groups
of
monkeys
and
as
a
function
of
sex.
Collins
et
al.
(2005,
2007)
have
shown
that
the
ascending
limb
of
the
quinpirole
dose‐response
curve
is
mediated
by
D3
receptors
while
the
descending
limb
is
mediated
by
D2
receptors.
Based
on
previous
experiments
in
rhesus
monkeys
(Martelle
et
al.
2007)
the
dose
range
of
quinpirole
administered
in
the
present
study
is
situated
on
the
ascending
limb
of
the
dose‐response
curve
and
therefore
is
thought
to
assess
primarily
100
D3
receptor
function.
The
greater
ability
of
quinpirole
to
elicit
yawning
in
the
prenatally
cocaine‐exposed
monkeys
is
similar
to
results
from
Moody
et
al.
(1992),
who
demonstrated
that
rat
pups
exposed
to
cocaine
throughout
gestation
exhibited
a
supersensitivity
to
the
stimulating
effects
of
quinpirole
with
respect
to
behaviors
such
as
forward
locomotion,
rearing
and
directed
oral
movements
compared
to
control
pups.
Additionally,
when
all
monkeys
prenatally
exposed
to
cocaine
were
used
in
the
analysis,
we
found
that
D3
receptor
sensitivity
correlated
with
the
maximum
dose
of
cocaine
each
individual
monkey
received
in
utero.
Taken
together,
the
present
results
provide
evidence
for
long‐term
neuropharmacological
consequences
of
prenatal
cocaine
exposure
on
D3
receptor
function
under
conditions
in
which
no
difference
in
D2‐like
receptors
was
observed
using
PET
imaging.
The
combination
of
effects
lead
to
interesting
hypotheses
regarding
differential
sensitivity
to
the
reinforcing
effects
of
cocaine.
For
example,
because
PET
imaging
studies
in
monkeys
have
shown
a
relationship
between
D2
receptor
availability
and
cocaine
reinforcement
(see
Nader
et
al.
2008),
the
PET
imaging
data
would
suggest
no
differences
between
prenatal
cocaine
exposed
and
control
monkeys
in
vulnerability
to
cocaine
reinforcement.
However,
D3
receptor
sensitivity
has
been
associated
with
impulsivity
(e.g.
Dodd
et
al.
2005;
Sokoloff
et
al.
2006),
which
would
suggest
differential
sensitivity
of
cocaine‐exposed
monkeys
compared
to
controls
in
acquisition
of
cocaine
self‐administration.
Additional
behavioral
studies
in
these
monkeys,
including
assessing
the
reinforcing
effects
of
cocaine,
will
provide
101
important
information
as
to
the
long‐term
consequences
of
prenatal
cocaine
exposure
and
the
role
of
D2‐like
receptor
subtypes
in
these
behavioral
outcomes.
In
an
effort
to
more
fully
characterize
DA
receptor
activity
in
vivo,
functional
studies
of
the
D1‐like
receptor
were
also
undertaken
in
these
same
monkeys.
D1‐like
receptor
densities
have
previously
been
shown
to
be
affected
by
chronic
cocaine
exposure
in
adult
monkeys
(Moore
et
al.
1998)
and
not
necessarily
in
a
manner
similar
to
the
effects
of
cocaine
on
D2‐like
receptors
(Nader
et
al.
2002).
Fang
et
al.
(1997)
reported
that
cocaine
treatment
from
gestational
day
22
to
70
resulted
in
significant
increases
in
D1‐like
receptor
densities
in
day‐70
fetal
monkey
striatum.
In
rodent
and
rabbit
models,
several
studies
suggest
that
prenatal
cocaine
exposure
uncoupled
the
D1
receptor
from
its
G‐protein
resulting
in
an
attenuation
of
D1
receptor
signaling
(Friedman
et
al.
1996;
Wang
et
al.
1995;
Lidow
1998;
Jones
et
al.
2000;
Unterwald
et
al.
2003).
However,
there
are
no
data
assessing
D1‐like
receptor
function
in
adults
who
had
been
prenatally
exposed
to
cocaine.
In
the
present
study,
no
differences
in
potency
or
effects
of
SKF
81297‐elicited
eye
blinks
were
observed
in
adult
monkeys
prenatally
exposed
to
cocaine
versus
controls.
Because
it
has
been
argued
that
this
unconditioned
behavior
is
a
sensitive
measure
of
D1‐like
signaling
(Jutkiewicz
and
Bergman
2004),
these
data
suggest
that
any
functional
differences
in
D1
receptor
sensitivity
observed
in
prenatally
cocaine‐exposed
animals
shortly
after
birth
are
no
longer
apparent
in
these
animals
as
adults.
102
It
should
be
noted
that
under
other
conditions
in
socially
housed
monkeys,
SKF
81297‐elicited
eye
blinking
did
not
differentiate
monkeys
based
on
social
rank
(Czoty
et
al.
2004),
even
though
differences
in
sensitivity
to
cocaine
reinforcement
were
observed
(Czoty
et
al.
2005).
It
remains
possible
that
other
functional
measures
of
D1‐like
receptor
activity
(e.g.,
drug
discrimination
or
drug
self‐administration)
may
yield
differential
sensitivity
due
to
prenatal
cocaine
exposure.
The
present
findings
are
also
the
first
to
note
sex
differences
in
sensitivity
to
the
D1‐like
agonist
effects
elicited
by
SKF
81297.
It
is
important
to
note
that
D3
receptor
function
(quinpirole‐
elicited
yawning)
was
also
differentially
affected
by
sex.
The
present
findings
add
to
a
growing
body
of
evidence
for
sex
differences
in
the
behavioral
effects
of
drugs.
Taken
together,
these
findings
indicate
that
prenatal
cocaine
exposure
can
have
long‐lasting
effects
on
DA
receptor
function
and
that
males
and
females
are
equally
sensitive
to
these
perturbations.
ACKNOWLEDGMENTS
This
research
was
supported
by
National
Institute
on
Drug
Abuse
grants
R01
DA25120,
R37
DA10584,
and
K31
DA024485.
The
authors
report
no
conflict
of
interest
and
would
like
to
acknowledge
the
technical
assistance
of
Tonya
Calhoun,
Kimberly
Black,
Holly
Smith
and
Whitney
Wilson.
The
authors
also
thank
Dr.
Merle
Paule
for
providing
information
related
to
the
histories
of
these
monkeys
and
Dr.
Anthony
Liguori
for
statistical
consultation.
103
FIGURE
1.
Distribution
volume
ratios
(DVRs)
of
[18F]FCP
in
control
(open
symbols)
and
prenatally
cocaine‐exposed
(shaded
symbols)
monkeys
in
the
caudate
nucleus,
putamen,
and
amygdala.
Each
bar
represents
mean
±
SEM
values
from
10
monkeys.
104
105
FIGURE
2.
Yawning
induced
by
quinpirole
(0.03‐0.3
mg/kg)
in
female
(A)
and
male
(B)
control
(open
symbols)
and
prenatally
cocaine‐exposed
(closed
symbols)
adult
rhesus
monkeys.
Panel
C
represents
mean
data
(male
and
female)
for
each
group.
Data
are
represented
as
the
mean
±
SEM
number
of
yawns
in
a
30‐min
observation
period.
106
FIGURE
3.
Relationship
between
peak
number
of
yawns
elicited
by
quinpirole
and
maximal
daily
dose
of
cocaine
received
in
utero
(from
Morris
et
al.,
1996).
Different
symbols
represent
males
(triangles)
and
females
(circles).
107
108
FIGURE
4C.
Effects
of
SKF
81297
on
rate
of
eye
blinking
in
control
(A)
and
prenatally
cocaine‐exposed
(B)
male
(filled
symbols)
and
female
(open
symbols)
monkeys.
Panel
C
represents
mean
data
(male
and
female)
for
each
group.
Each
point
represents
mean
±
SEM
values.
109
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RM,
Strupp
BJ
(2000)
Prenatal
cocaine
exposure
increases
sensitivity
to
the
attentional
effects
of
the
dopamine
D1
agonist
SKF81297.
J
Neurosci
20:8902‐8908.
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114
CHAPTER
III
INCREASED
IMPULSIVITY
IN
MALE,
BUT
NOT
FEMALE,
ADULT
RHESUS
MONKEYS
EXPOSED
TO
COCAINE
THROUGHOUT
GESTATION
Lindsey
R.
Hamilton,
Paul
W.
Czoty,
Michael
A.
Nader
The
following
manuscript
was
submitted
to
Psychopharmacology
in
April
2010.
Stylistic
variations
are
due
to
the
requirements
of
the
journal.
Lindsey
R.
Hamilton
performed
the
experiments,
analyzed
the
data,
and
prepared
the
manuscript.
Paul
W.
Czoty
and
Michael
A.
Nader
acted
in
an
advisory
and
editorial
capacity.
115
ABSTRACT
RATIONALE:
In
utero
cocaine
exposure
has
been
associated
with
alterations
in
the
dopamine
(DA)
system
in
monkeys.
However,
the
behavioral
outcomes
of
prenatal
cocaine
exposure
in
adulthood
are
poorly
understood.
OBJECTIVES:
To
assess
behavioral
measures
of
impulsivity
in
14
year‐old
rhesus
monkeys
exposed
to
cocaine
in
utero
and
controls
(n=10
per
group).
MATERIALS
AND
METHODS:
To
assess
impulsivity,
two
unconditioned
behavioral
tasks,
novel
object
reactivity
and
locomotor
activity,
and
two
conditioned
behavioral
tasks,
response
extinction
and
delay
discounting,
were
examined.
In
addition,
cerebrospinal
fluid
(CSF)
samples
were
analyzed
for
concentrations
of
the
monoamine
metabolites
homovanillic
acid
(HVA)
and
5‐hydroxyindoleacetic
acid
(5‐HIAA).
RESULTS:
No
differences
in
CSF
concentrations
of
5‐HIAA
and
HVA,
latencies
to
touch
a
novel
object
or
locomotor
activity
were
observed
between
groups
or
sexes.
However,
prenatally
cocaine‐exposed
monkeys
required
a
significantly
greater
number
of
sessions
to
reach
criteria
for
extinction
of
food‐reinforced
behavior
than
control
monkeys.
On
the
delay‐discounting
task,
male
prenatally
cocaine‐
exposed
monkeys
had
a
significantly
larger
mean
indifference
point
than
male
control
monkeys;
no
differences
were
observed
in
females.
When
an
overall
impulsivity
score
was
determined
taking
into
account
the
two
unconditioned
and
two
conditioned
behavioral
measures,
male
prenatally
cocaine‐exposed
monkeys
were
more
impulsive
than
male
control
monkeys.
No
differences
in
overall
impulsivity
were
observed
in
females.
A
significant
116
negative
correlation
between
CSF
concentration
of
HVA
and
overall
impulsivity
score
was
observed.
CONCLUSIONS:
These
findings
suggest
that
prenatal
cocaine
exposure
has
long‐term
neurobehavioral
deficits
with
neurobiological
correlates
that
are
influenced
by
sex
of
the
individual.
KEYWORDS:
Prenatal
cocaine
–
Impulsivity
–
Delay
discounting
–
CSF–
HVA
–
Rhesus
monkey
117
Maternal
cocaine
addiction
is
a
significant
public
health
problem
with
almost
50,000
infants
born
each
year
having
been
exposed
to
cocaine
in
utero
(National
Pregnancy
and
Health
Survey
1996).
Several
investigators
have
examined
the
physiological
consequences
of
cocaine
use
throughout
gestation
in
nonhuman
primate
models
(e.g.
Howell
et
al.
2001;
Lidow
2003).
The
present
study
utilized
prenatal
cocaine
exposure
in
rhesus
monkeys
in
order
to
evaluate
the
behavioral
and
neurochemical
consequences
of
in
utero
drug
exposure
in
adults.
These
animals
had
been
exposed
to
cocaine
throughout
the
25
weeks
of
gestation
or
were
controls
(Morris
et
al.
1996,
1997)
and
were
studied
as
adults
(14‐15
years
old).
We
recently
examined
dopamine
(DA)
receptor
function
in
these
adult
monkeys
(Hamilton
et
al.
2010)
using
agonist‐elicited
behaviors
and
PET
imaging.
There
were
no
differences
in
DA
D1‐
and
D2‐like
receptor
function,
but
differences
were
noted
in
the
behavioral
effects
of
the
D3/D2
agonist
quinpirole
in
monkeys
prenatally
exposed
to
cocaine.
In
the
present
study,
we
extended
the
examination
of
neurobiological
characteristics
to
include
CSF
concentrations
of
the
DA
metabolite
homovanillic
acid
(HVA)
and
the
serotonin
metabolite
5‐hydroxyindole
acetic
acid
(5‐HIAA),
and
extended
behavioral
assessments
to
measures
thought
to
reflect
aspects
of
impulsivity.
Cocaine
use
during
pregnancy
has
been
associated
with
physical
deficits
in
the
offspring
including
reduced
body
weight,
body
length,
and
head
circumference
of
the
infants
at
birth
(Nair
and
Watson
1991)
and
developmental
deficits
including
memory
(Singer
et
al.
2005,
2008),
118
attention
(Singer
et
al.
2000;
Noland
et
al.
2005;
Linares
et
al.
2006),
cognition
(Singer
et
al.
2001;
Morrow
et
al.
2006),
and
impulse
control
(Savage
et
al.
2005;
Linares
et
al.
2006;
Accornero
et
al.
2007;
Pulsifer
et
al.
2008).
Investigating
the
differences
in
impulse
control
in
a
highly
controlled
animal
model
is
an
important
complement
to
the
human
studies.
However,
some
of
the
difficulty
in
evaluating
impulsivity
is
due
to
it
being
conceptualized
as
a
broad
spectrum
of
behaviors
rather
than
a
single
trait
(Moeller
et
al.
2001;
Chamberlain
and
Sahakian
2007).
While
research
with
humans
has
typically
assessed
impulsivity
using
standardized
questionnaires
(Evenden
1999),
there
is
no
agreement
on
how
to
measure
impulsivity
in
animal
models.
Several
distinct
measures
have
been
developed
to
assess
impulsivity
in
animals,
including
response
to
novelty,
locomotor
activity,
behavioral
inhibition,
and
choice
between
an
immediate,
low‐magnitude
reward
over
a
delayed
large‐magnitude
reward.
In
the
present
study,
each
of
these
dependent
variables
was
assessed
to
directly
compare
these
various
measures
of
impulsivity.
The
first
set
of
behavioral
measures
to
assess
impulsivity
used
in
the
present
study
involved
the
unconditioned
behaviors
of
response
to
a
novel
object
(Dellu
et
al.
1996;
Zuckerman
1996)
and
locomotor
activity
in
an
open
field.
Reactivity
to
a
novel
object
has
been
used
as
a
measure
of
impulsivity
in
rodents
(Hooks
et
a.
1991;
Suto
et
al.
2001;
Davis
et
al.
2008)
and
nonhuman
primates
(Bolig
et
al.
1992;
reviewed
in
Clarke
and
Boinski
1995;
Coleman
et
al.
2005;
Czoty
et
al.
2010).
Regarding
locomotor
activity,
Piazza
and
119
colleagues
demonstrated
that
responsiveness
in
an
open
field
was
associated
with
vulnerability
to
stimulant
self‐administration
(Piazza
et
al.
1989;
1990;
reviewed
in
Piazza
and
Le
Moal
1998).
Interestingly
Dalley
et
al.
(2007)
did
not
find
a
relationship
between
locomotor
activity
and
other
measures
of
impulsivity.
In
the
present
study,
we
directly
compared
locomotor
activity
of
adult
rhesus
monkeys
with
several
other
measures
hypothesized
to
assess
impulsivity.
A
third
measure
of
impulsivity
is
response
perseveration,
which
is
the
tendency
to
continue
emitting
a
formerly
reinforced
response
despite
the
response
currently
being
either
unrewarded
or
punished
(McCleary
1966).
It
is
thought
that
response
perseveration
is
a
measure
of
deficient
behavioral
inhibition
because
in
these
tasks
subjects
must
stop
their
ongoing
behavior
(Matthys
et
al.
1998).
In
the
present
study,
perseverative
responding
was
assessed
by
examining
responding
during
extinction
of
previously
food‐
reinforced
fixed‐ratio
(FR)
responding
in
monkeys
and
subjects
requiring
a
greater
number
of
sessions
to
extinguish
responding
(unrewarded
responding)
was
classified
as
more
impulsive
than
subjects
that
took
fewer
sessions
to
extinguish
responding.
As
a
final
measure
of
impulsivity,
we
assessed
choice
behavior
involving
delays.
Impulsive
choice
is
most
commonly
assessed
in
human
studies
using
a
delay‐discounting
task
in
which
subjects
are
asked
to
choose
between
a
small,
immediate
reinforcer
and
a
larger,
delayed
reinforcer.
The
subjective
value
of
the
larger
reinforcer
is
decreased
(i.e.,
discounted)
as
the
120
length
of
time
the
subject
must
wait
to
receive
it
increases.
By
using
a
series
of
choices
between
varying
delay
values,
an
indifference
point
can
be
calculated
as
the
delay
value
at
which
the
smaller,
immediate
reinforcer
is
chosen
as
often
as
the
larger,
delayed
reinforcer.
Delay
discounting
has
been
adapted
for
animal
studies
(e.g.
Perry
et
al.
2005;
Woolverton
et
al.
2007).
Although
several
studies
have
examined
delay
discounting
in
monkeys
(Anderson
and
Woolverton
2003;
Woolverton
and
Anderson
2006;
Woolverton
et
al.
2007;
Newman
et
al.
2008),
these
studies
have
involved
choice
between
drug
reinforcers.
The
present
study
extended
this
work
to
delay
discounting
involving
different
magnitudes
of
non‐drug
reinforcers.
Such
information
allows
for
the
general
assessment
of
impulsivity
and
allows
for
delay
discounting
values
to
be
compared
to
other
non‐drug
related
behavioral
measures
of
impulsivity.
Finally,
in
addition
to
these
behavioral
measures,
we
examined
the
relationship
between
measures
of
DA
receptor
function
and
monoamine
metabolite
levels
and
the
various
measures
of
impulsivity
in
both
male
and
female
monkeys.
MATERIAL
AND
METHODS
SUBJECTS.
Twenty
adult
rhesus
monkeys
(Macaca
mulatta),
born
between
1993
and
1995
and
raised
at
the
FDA
facility
in
Little
Rock,
AR
until
their
arrival
at
Wake
Forest
University
in
2007,
served
as
subjects.
Ten
monkeys
(6
male,
4
female)
were
prenatally
exposed
to
cocaine
and
10
monkeys
(5
male,
5
female)
were
prenatally
exposed
to
saline,
as
described
previously
121
(Morris
et
al.
1996,
1997).
Briefly,
the
mothers
of
the
monkeys
used
in
this
study
received
intramuscular
injections
of
saline
or
escalating
doses
of
cocaine
three
times
per
day
for
the
entire
course
of
gestation,
with
mean
cumulative
cocaine
intake
of
1131.3
(±
56.1
SEM)
mg/kg
(Morris
et
al.
1996).
When
the
monkeys
were
6
months
of
age,
they
were
housed
individually
in
the
same
colony
room
and
began
behavioral
training
involving
an
operant
test
battery
(Morris
et
al.
1997).
Other
than
their
prenatal
drug
histories,
all
monkeys
had
nearly
identical
experimental
histories
(see
Paule
et
al.
1996;
Morris
et
al.
1996).
At
the
start
of
this
experiment,
monkeys
were
individually
housed
in
stainless‐steel
cages
with
water
available
ad
libitum
and
had
visual
and
auditory
contact
with
each
other.
Since
we
have
previously
shown
that
monoamine
function
is
influenced
by
menstrual
cycle
(Czoty
et
al.
2009),
we
monitored
menstrual
cycle
phase
throughout
the
experiment
by
daily
vaginal
swabs.
Days
of
bleeding
were
recorded
as
indicative
of
menses.
During
quarantine,
a
free‐feeding
weight
was
determined
and
monkeys’
body
weights
were
maintained
at
approximately
95%
of
that
value
throughout
these
studies
(LabDiet
Monkey
Chow
and
fresh
fruit).
Each
monkey
was
fitted
with
an
aluminum
collar
(Primate
Products,
Redwood
City,
CA)
and
trained
to
sit
calmly
in
a
standard
primate
chair
(Primate
Products)
using
a
specially
designed
stainless‐steel
pole
that
attached
to
the
collar.
All
manipulations
were
performed
in
accordance
with
the
2003
National
Research
Council
Guidelines
for
the
Care
and
Use
of
Mammals
in
Neuroscience
and
Behavioral
Research
and
were
approved
by
the
122
Wake
Forest
University
Institutional
Animal
Care
and
Use
Committee.
The
order
of
experiments
accurately
depicts
the
order
of
testing
for
each
monkey.
APPARATUS.
The
apparatus
consisted
of
a
ventilated,
sound‐attenuating
chamber
(1.5
x
0.74
x
0.76
m;
Med
Associates,
East
Fairfield,
VT)
designed
to
accommodate
a
primate
chair.
Two
response
keys
(5
cm
wide)
were
located
on
one
side
of
the
chamber
with
a
horizontal
row
of
three
stimulus
lights
14
cm
above
each
response
key
and
a
food
receptacle
was
located
between
the
response
keys.
The
receptacle
was
connected
with
tygon
tubing
to
a
pellet
dispenser
(Gerbarands
Corp.,
Arlington,
MA)
located
on
the
top
of
the
chamber
for
delivery
of
1‐g
banana‐flavored
food
pellets
(P.K.
Noyes
Co.,
Lancaster,
NH).
An
infusion
pump
(Cole‐Palmer,
Inc.,
Chicago,
IL)
was
located
on
the
top
of
the
chamber.
SURGERY.
Each
monkey
was
prepared
with
a
chronic
indwelling
venous
catheter
and
subcutaneous
vascular
port
(Access
Technologies,
Skokie,
IL)
under
sterile
surgical
conditions.
Anesthesia
was
induced
and
maintained
with
ketamine
(15
mg/kg)
and
butorphanol
(0.025
mg/kg).
Vital
signs
were
monitored
for
the
duration
of
the
surgery.
Briefly,
a
catheter
was
inserted
into
the
femoral
vein
to
the
level
of
the
vena
cava.
The
distal
end
of
the
catheter
was
passed
subcutaneously
to
a
point
slightly
off
the
midline
of
the
back,
where
an
incision
was
made.
The
end
of
the
catheter
was
then
attached
to
the
vascular
access
port
and
placed
in
a
pocket
formed
by
blunt
dissection.
123
Each
port
and
catheter
was
filled
with
heparinized
saline
solution
(100
Units/ml)
after
every
experimental
session
to
prolong
the
patency.
Prior
to
each
saline
self‐administration
session,
the
back
of
the
animal
was
cleaned
with
betadine
and
95%
EtOH
and
the
port
was
connected
to
the
infusion
pump
located
outside
the
chamber
via
a
20‐gauge
Huber
Point
Needle
(Access
Technologies).
The
pump
was
operated
for
approximately
3
sec
to
fill
the
port
and
catheter
line
with
saline
prior
to
starting
the
session.
CEREBROSPINAL
FLUID
(CSF)
MEASURES
OF
5­HIAA
AND
HVA.
Monkeys
were
anesthetized
with
10
mg/kg
ketamine,
the
aluminum
collar
was
removed
and
the
neck
and
the
back
of
the
skull
were
shaved
and
cleaned
with
betadine
and
95%
EtOH.
A
25‐gauge,
1.5‐inch
needle
attached
to
a
3‐ml
syringe
was
inserted
through
the
cisterna
magna
and
approximately
2
ml
of
CSF
was
removed
within
10
min
of
induction
of
anesthesia.
Females
were
studied
only
during
the
follicular
phase.
The
samples
were
immediately
transferred
to
vacutainer
tubes
on
ice.
Samples
were
centrifuged
at
4º
C
for
30
min
at
3000
rpm
and
then
aliquoted
into
microcentrifuge
tubes
for
storage
at
‐30º
C
until
they
were
analyzed
using
high‐pressure
liquid
chromatography
with
electrochemical
detection.
The
mobile
phase
consisted
of
9.6
g
citric
acid,
11.2
g
sodium
phosphate
monobasic
and
0.7
g
1‐
octanesulfonic
acid
in
860
ml
of
ultra‐pure
water.
100
microliters
of
0.5
M
ethylenediaminetetraacetic
acid
(EDTA)
was
added
and
the
pH
of
the
solution
was
adjusted
to
3.
Next,
6
drops
of
triethylamine
and
140
ml
124
acetonitrile
were
added
and
the
mobile
phase
was
filtered
twice.
Mobile
phase
was
delivered
to
the
system
at
a
rate
of
0.2
ml/min
using
an
ESA
582
solvent
delivery
module
(ESA
Inc.,
Chelmsford,
MA).
Three
30‐microliter
aliquots
of
each
sample
were
loaded
into
a
ESA
542
autoinjector
and
20
microliters
were
injected.
Separation
was
achieved
with
a
C‐18
column
(150
mm
length,
3.2
mm
i.d.,
3
micrometer
particle
size;
ESA,
Inc.)
and
5‐HIAA
and
HVA
were
detected
in
samples
using
an
ESA
Coulochem
II
detector.
Concentrations
of
5‐HIAA
and
HVA
were
determined
by
interpolation
using
a
standard
curve
that
was
generated
using
standard
solutions
containing
known
amounts
of
the
metabolites.
Each
sample
was
tested
in
triplicate
and
average
values
were
used
for
data
analysis.
EXPERIMENT
1:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
IMPULSIVITY
USING
UNCONDITIONED
BEHAVIORS.
Approximately
2‐6
months
after
quarantine
ended,
monkeys
were
characterized
on
two
measures
of
impulsivity
that
utilized
unconditioned
behaviors.
For
the
novel
object
reactivity
test,
the
monkey
in
the
cage
adjacent
to
the
subject’s
home
cage
was
removed,
the
partition
was
removed
from
between
the
cages,
and
the
subject
was
moved
to
the
adjacent
cage.
Next,
the
partition
was
replaced
and
an
opaque
black
Plexiglas
box
measuring
30.5
x
20.3
x
20.3
cm
was
placed
in
the
monkey’s
empty
home
cage.
The
partition
was
removed
again
and
the
latency
to
touch
the
object
was
recorded.
If
the
monkey
did
not
touch
the
object
within
15
min,
a
score
of
900
sec
was
assigned.
All
sessions
were
125
videotaped
and
scored
by
an
observer
blind
to
the
monkey’s
prenatal
condition.
The
900‐sec
maximum
duration
was
based
on
data
from
our
laboratory
(Riddick
et
al.
2009).
To
assess
locomotor
activity,
each
monkey
was
placed
in
a
3.0
x
2.0
x
1.75
m
enclosure
with
the
field
divided
into
9
equal
grid
zones.
Over
the
30
minute
test
period,
the
monkeys’
activity
was
videotaped
using
a
camera
mounted
overhead.
The
primary
dependent
measure
was
crossings
between
the
zones,
defined
as
>50%
of
the
monkey’s
body
crossing
into
a
new
grid
section,
and
was
counted
by
an
observer
blind
to
the
prenatal
condition
of
the
monkey.
EXPERIMENT
2:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
RESPONSE
EXTINCTION.
Monkeys
were
initially
trained
to
respond
on
the
left
and
right
keys
by
reinforcing
each
response
with
a
1‐g
banana‐flavored
pellet;
a
30‐sec
timeout
followed
each
food
presentation.
The
light
above
the
response
key
signaled
food
availability;
only
one
key
was
active
during
a
session.
Over
the
course
of
2‐3
weeks,
the
number
of
responses
required
was
increased
until
a
FR
30
schedule
of
food
presentation
was
achieved.
Sessions
ended
after
30
reinforcers
had
been
delivered
or
60
min
had
elapsed.
When
responding
was
reliably
maintained
(i.e.,
mean
response
rate
±
20%
for
3
consecutive
sessions)
on
both
keys
and
maximal
food
reinforcement
was
obtained
consistently,
intravenous
catheters
were
implanted.
126
After
implantation
of
the
catheter,
baseline
food
reinforcement
rates
were
re‐
established
over
5
sessions,
but
only
on
the
response
key
associated
with
the
highest
rates.
For
control
monkeys,
4
had
higher
rates
on
the
left
key
and
6
on
the
right
key
and
for
prenatally
cocaine‐exposed
monkeys
the
distribution
was
3
on
the
left
key
and
7
on
the
right
key.
Saline
injections
were
substituted
for
food
pellets
for
at
least
5
consecutive
sessions
and
until
responding
was
deemed
extinguished.
The
criteria
for
extinguishing
food‐
reinforced
responding
were
3
consecutive
sessions
in
which
response
rates
were
reduced
by
at
least
80%
of
baseline
food
reinforced
responding
(i.e.,
mean
response
rate
±
20%
for
3
consecutive
sessions)
with
no
trends
in
responding.
The
primary
dependent
measure
was
the
number
of
sessions
to
meet
these
criteria.
EXPERIMENT
3:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
DELAY
DISCOUNTING.
Monkeys
were
re‐exposed
to
the
FR
30
schedule
of
food
presentation,
with
each
pellet
delivery
followed
by
a
30‐sec
timeout
(TO).
At
the
start
of
the
session,
one
light
above
one
response
key
was
illuminated
to
indicate
it
was
active;
the
order
of
which
key
was
active
varied
across
sessions.
Sessions
ended
after
30
reinforcers
were
received
or
60
min
elapsed.
Subjects
responded
under
these
conditions
until
responding
on
the
right
and
left
response
key
was
reliably
maintained
and
was
deemed
stable
on
each
lever
(i.e.,
mean
response
rate
±
20%
for
3
consecutive
sessions).
127
The
conditions
were
then
changed
to
a
concurrent
schedule,
which
served
as
the
schedule
of
reinforcement
for
the
delay
discounting
procedure.
The
choice
was
initially
between
1
and
3
food
pellets
delivered
immediately
after
completion
of
the
FR
30
requirement.
The
1
pellet
reinforcer
was
contingent
on
responding
on
the
key
associated
with
the
highest
rates,
while
responding
on
the
other
key
delivered
3
pellets.
Initially,
the
delay
value
associated
with
both
reinforcers
was
0
sec.
The
delay
value
associated
with
1
pellet
remained
at
0
sec
throughout
the
experiment,
while
the
delay
associated
with
3
pellet
reinforcer
varied
from
5‐300
sec.
Sessions
began
with
two
forced‐choice
(i.e.,
sampling)
trials.
During
these
sampling
trials,
only
one
response
key
was
active
with
illumination
of
the
light
and
completion
of
the
FR
30
resulted
in
the
reinforcer
and
delay.
After
a
30‐sec
TO,
the
other
response
key
was
illuminated
and
completion
of
the
FR
resulted
in
the
reinforcer
and
delay.
For
the
duration
of
the
delay,
a
red
light
above
the
response
key
flashed
on
and
off
each
second.
Once
both
sampling
trials
were
completed
and
following
a
30‐sec
TO,
the
schedule
changed
to
a
concurrent
schedule
with
both
response
keys
being
active.
To
limit
the
influence
of
response
perseveration,
a
forced
choice
was
implemented
during
the
session
if
the
monkey
chose
the
same
lever
5
times
in
a
row
and
then
returned
to
a
concurrent
schedule.
Delay
values
were
kept
constant
for
at
least
5
consecutive
sessions,
and
until
the
percent
choice
of
the
larger,
delayed
reinforcer
was
deemed
stable
(mean
percent
choice
±
20%
for
3
consecutive
sessions).
Sessions
terminated
after
30
free
choices
were
128
completed
or
60
min
had
elapsed.
Delay
values
were
presented
in
a
quasi‐
random
order
to
determine
a
delay‐percent
choice
larger
reinforcer
curve.
Based
on
each
monkey’s
individual
curve,
the
indifference
point
(delay
value
that
engendered
50%
choice
of
the
larger,
delayed
reinforcer
and
50%
choice
of
the
smaller,
immediate
reinforcer)
was
calculated.
The
primary
dependent
measure
for
this
experiment
was
the
indifference
point.
DATA
ANALYSIS.
CSF
concentrations,
latency
to
approach
a
novel
object,
locomotor
activity,
responding
during
extinction,
and
the
indifference
point
(from
delay
discounting)
were
each
analyzed
using
a
two‐way
ANOVA
using
Group
(Prenatal
Cocaine
and
Saline)
and
Sex
as
Factors.
Post‐hoc
Bonferroni’s
tests
were
conducted
when
significant
main
effects
were
indicated
by
the
ANOVA.
For
some
dependent
variables,
data
were
analyzed
using
Spearman’s
correlation
coefficient
for
ranked
data.
In
all
cases,
significance
was
accepted
at
the
95%
level
of
confidence
(p
<
0.05).
At
the
end
of
all
the
experiments,
the
data
were
collated
and
an
overall
impulsivity
score
was
calculated.
To
determine
this
index,
all
20
monkeys
were
ranked
from
20
(most
impulsive)
to
1
(least
impulsive)
on
each
dependent
variable
(latency
to
touch
a
novel
object,
locomotor
activity,
number
of
sessions
to
reach
extinction
criteria,
and
indifference
point
from
delay
discounting)
and
the
average
rankings
across
all
tasks
was
calculated.
These
data
were
analyzed
using
a
Mann‐Whitney
test
and
correlated
with
CSF
concentrations
using
Spearman’s
correlation
coefficient.
129
RESULTS
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
CSF
MEASURES
OF
5­HIAA
AND
HVA.
A
two‐way
ANOVA
indicated
no
significant
effect
of
prenatal
condition,
sex
or
an
interaction
on
CSF
concentrations
of
5‐HIAA
and
HVA
(Table
1).
EXPERIMENT
1:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
IMPULSIVITY
USING
UNCONDITIONED
BEHAVIORS.
A
two‐way
ANOVA
revealed
no
significant
main
effect
of
prenatal
cocaine
exposure
or
sex
and
no
significant
interaction
on
latency
to
approach
a
novel
object
(Fig.
1A).
Because
there
were
no
differences
due
to
prenatal
drug
exposure,
mean
latencies
for
all
the
males
were
compared
to
mean
latencies
for
the
females
and
were
not
significantly
different.
Locomotor
activity
ranged
from
5‐316
counts
over
the
30
min
exposure
and
did
not
differ
as
a
function
of
prenatal
exposure
or
sex
and
there
was
no
significant
interaction
(Fig.
1B).
EXPERIMENT
2:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
EXTINGUISHING
FOOD
REINFORCED
BEHAVIOR.
Under
baseline
conditions,
mean
response
rates
under
the
FR
30
schedule
of
food
presentation
were
not
different
in
male
monkeys
with
mean
(±
SEM)
values
of
3.89
(±
0.68)
and
2.46
(±
0.54)
resp/sec
for
control
and
prenatally
cocaine‐exposed
monkeys,
respectively.
Similarly,
female
monkeys
did
not
differ
in
mean
response
rates
130
between
groups
(1.60
±
0.30
and
2.64
±
1.16
resp/sec,
for
control
and
prenatally
cocaine‐exposed
monkeys,
respectively).
Response
extinction
was
studied
by
substituting
saline
for
food
presentation.
A
two‐way
ANOVA
revealed
a
significant
main
effect
of
prenatal
cocaine
exposure
(F(1,17)=4.78,
p=0.04)
but
no
significant
effect
of
sex
and
no
significant
interaction
on
number
sessions
to
reach
criteria
for
response
extinction.
Prenatally
cocaine‐
exposed
monkeys
required
a
greater
number
of
sessions
to
reach
criteria
for
extinguishing
food‐reinforced
responding
than
control
monkeys
(Fig.
2).
EXPERIMENT
3:
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
DELAY
DISCOUNTING.
Under
the
concurrent
schedule,
when
the
delay
was
0
sec,
monkeys
chose
the
larger
magnitude
food
reinforcer
on
nearly
100%
of
the
trials
(see
Fig.
3
for
representative
curves).
On
average,
response
rates
were
higher
on
the
key
associated
with
the
larger
magnitude
of
food
reinforcement
(1.56
±
0.28
resps/sec
and1.72
±
0.23
resps/sec
for
the
1
pellet‐
and
3
pellet‐associated
keys,
respectively).
Response
rates
did
not
differ
between
prenatally
cocaine
exposed
and
control
monkeys
nor
between
male
and
female
monkeys
and
response
rates
did
not
change
significantly
from
baseline
at
any
delay
value
(Table
2).
Increases
in
the
delay
value
resulted
in
time‐dependent
reductions
in
the
percent
of
trials
in
which
the
larger
reinforcer
was
chosen
(Fig.
3).
Indifference
points
were
calculated
as
the
delay
value
(sec)
that
engendered
50%
choice
of
the
larger,
delayed
reinforcer
and
the
smaller,
immediate
reinforcer
(Fig.
4).
A
two‐way
ANOVA
131
revealed
a
signficant
effect
of
prenatal
cocaine
exposure
[F(1,
16)=10.56,
p=0.005]
and
a
significant
interaction
between
prenatal
condition
and
sex
[F(1,
16)=4.8,
p=0.04].
Post‐hoc
Bonferroni
tests
indicated
that
male
prenatally
cocaine‐exposed
monkeys
had
significantly
shorter
indifference
points
than
male
control
monkeys
(p=0.01),
while
there
was
no
difference
between
female
control
and
prenatally
cocaine
exposed
monkeys
(Fig.
4).
EFFECTS
OF
PRENATAL
COCAINE
EXPOSURE
ON
OVERALL
IMPULSIVITY.
In
order
to
characterize
each
monkey
across
the
various
dependent
variables,
on
overall
impulsivity
score
was
calculated
(see
Methods).
Based
on
these
values,
male
prenatally
cocaine‐exposed
monkeys
were
more
impulsive
than
male
control
monkeys
(p=0.009),
whereas
there
were
no
differences
observed
in
female
monkeys
(Fig.
5).
Spearman
correlation
analysis
revealed
that
scores
on
none
of
the
impulsivity
tasks
(i.e.,
novel
object
reactivity,
locomotor
activity,
response
extinction
and
delay
discounting)
correlated
with
scores
on
any
other
impulsivity
task
(data
not
shown).
However,
there
was
a
significant
negative
correlation
between
CSF
concentration
of
HVA
and
overall
impulsivity
score
(rs=‐0.45,
p=0.046);
no
significant
correlation
between
CSF
5‐HIAA
concentrations
and
impulsivity
scores
were
observed.
DISCUSSION
The
purpose
of
the
present
studies
was
to
extend
earlier
work
characterizing
adult
rhesus
monkeys
prenatally
exposed
to
cocaine
and
132
controls
to
include
neurochemical
correlates
and
behavioral
endpoints
related
to
measures
of
impulsivity.
To
accomplish
this,
CSF
concentrations
of
the
DA
metabolite
HVA
and
the
5‐HT
metabolite
5‐HIAA
were
obtained
from
10
cocaine‐exposed
and
10
control
monkeys.
In
addition,
several
unconditioned
and
conditioned
behaviors
believed
to
assess
aspects
of
impulsivity
were
examined.
Finally,
the
interaction
between
prenatal
drug
history
and
sex
of
the
monkey
on
these
various
measures
was
assessed.
There
were
no
differences
between
groups
or
sexes
in
CSF
concentrations
of
monoamine
metabolites
or
in
response
to
novelty
or
locomotor
activity.
In
contrast,
prenatally
cocaine‐exposed
monkeys
were
more
impulsive
than
control
monkeys
on
two
conditioned
behavioral
measures
of
impulsivity,
response
extinction
and
delay
discounting.
When
all
the
measures
were
combined
and
each
animal
was
assigned
an
“impulsivity
score”,
the
prenatally
cocaine‐exposed
male
monkeys
were
significantly
more
impulsive.
These
findings
suggest
differential
effects
of
prenatal
cocaine
exposure
on
measures
of
impulsivity
that
are
influenced
by
sex.
These
monkeys
represent
a
unique
cohort
of
animals
–
adult
male
and
female
Old
World
macaques
who
had
been
exposed
to
cocaine
throughout
the
25
weeks
of
gestation
(Morris
et
al.
1996)
and
grown
up
with
minimal
exposure
to
drugs
of
abuse.
Using
PET
imaging,
we
previously
reported
that
there
were
no
group
or
sex
differences
in
DA
D2‐like
receptor
availability
in
these
adults
(Hamilton
et
al.
2010).
Other
pharmacological
studies
revealed
no
differences
in
D1‐like
receptor
function,
but
significant
differences
related
133
to
prenatal
drug
exposure
and
sensitivity
to
DA
D3
agonist
effects.
Comparing
results
from
that
study
and
the
present
data,
there
is
a
significant
positive
correlation
between
overall
impulsivity
rank
and
peak
effects
of
yawning
elicited
by
the
D3
receptor
agonist
quinpirole
in
males
(rs=0.61,
p=0.04)
but
not
females
(data
not
shown).
Additionally,
a
one‐tailed
Spearman’s
correlation
found
that
in
male
subjects
impulsivity
ranking
was
negatively
correlated
(rs=
‐0.62,
p=0.046)
with
D2‐like
receptor
availability
in
the
caudate
nucleus
(from
Hamilton
et
al.
2010).
These
findings
suggest
that
long‐term
neuropharmacological
effects
due
to
prenatal
cocaine
exposure
can
have
behavioral
consequences,
especially
in
male
subjects.
The
present
findings
are
consistent
with
other
studies
showing
an
association
between
low
striatal
D2/D3
receptor
availability
and
impulsivity
in
human
methamphetamine‐dependent
subjects
(Lee
et
al.
2009)
and
in
rodents
(Dalley
et
al.
2007).
The
present
findings
also
support
the
idea
that
the
D3
receptor
could
be
a
promising
pharmacological
target
for
treating
impulsivity‐related
disorders,
including
substance
abuse
(for
reviews
see
Le
Foll
et
al.
2005;
Sokoloff
et
al.
2006;
Heidbreder
2008).
We
found
a
relationship
between
impulsivity
and
CSF
concentrations
of
the
DA
metabolite
HVA,
but
not
the
serotonin
metabolite
5‐HIAA,
in
contrast
to
the
extensive
literature
documenting
an
association
between
decreased
5‐HIAA
levels
and
increased
impulsivity
in
nonhuman
primates
(Higley
et
al.
1996;
Westergaard
et
al.
1999,
2003;
Fairbanks
et
al.
1999,
2001,
2004;
Manuck
et
al.
2003).
A
likely
explanation
for
the
discrepancy
134
between
findings
is
the
use
of
different
measures
of
impulsivity.
As
described
below,
the
construct
of
impulsivity
is
multi‐faceted,
such
that
differential
contribution
of
5‐HT
and
5‐HIAA
may
be
dependent
on
the
behavioral
measure.
Nonetheless,
these
data
suggest
that
5‐HT
is
not
necessarily
a
major
contributor
to
behaviors
deemed
impulsive.
The
relationship
we
observed
between
HVA
and
impulsivity
is
a
novel
finding
in
nonhuman
primates
and
concurs
with
a
recent
report
that
CSF
HVA
is
inversely
correlated
with
a
form
of
impulsivity
in
human
subjects
with
personality
disorder
(Coccaro
and
Lee
2010).
This
relationship
between
HVA
and
impulsivity
provides
further
evidence
that
alterations
in
the
dopaminergic
system
may
regulate
impulsivity.
The
present
findings
also
extended
our
earlier
work
by
showing
higher
levels
of
impulsivity
in
the
male
monkeys
exposed
to
cocaine
in
utero
but
not
in
females,
suggesting
differential
effects
of
prenatal
cocaine
exposure
influenced
by
sex.
Gender‐specific
effects
have
also
been
found
in
animal
studies
with
males
more
susceptible
to
the
negative
long‐term
effects
of
prenatal
cocaine
exposure
on
5‐HT
receptors
(Johns
et
al.
2002)
and
DA
receptor
binding
and
reactivity
(Silvers
et
al.
2006;
Dow‐Edwards
2010).
Additionally,
recent
clinical
studies
reported
males
to
be
more
adversely
affected
by
prenatal
cocaine
exposure
than
females,
specifically
increasing
their
risk
for
problems
of
inhibitory
control
(Delaney‐Black
et
al.
2004;
Bendersky
et
al.
2006;
Dennis‐Tiwary
et
al.
2006;
Bennet
et
al.
2007).
It
has
been
suggested
that
the
male
fetus
is
more
vulnerable
to
in
utero
stressors
135
and
neurotoxins
than
the
female
fetus
(Kraemer
2000)
which
may
account
for
the
larger
deficits
observed
in
prenatally
cocaine
exposed
males
than
females.
It
is
also
possible
that
other
changes
that
occur
during
hormonal
variations
of
adolescence
may
mask
effects
of
prenatal
cocaine
exposure
until
maturation
(Cabrera‐Vera
et
al.
2000).
Our
findings
of
increased
impulsivity
in
male,
but
not
female,
monkeys
exposed
to
cocaine
throughout
gestation
support
the
idea
that
prenatal
cocaine
exposure
outcomes
are
influenced
by
sex.
This
is
the
first
report
to
investigate
a
wide
range
of
impulsivity
measures
in
the
same
cohort
of
nonhuman
primates.
Behavioral
outcomes
from
the
four
tasks
used
in
this
study
(novel
object
reactivity,
locomotor
activity,
response
extinction
and
delay
discounting)
did
not
correlate
with
one
another,
indicating
that
we
were
measuring
different
facets
of
the
construct
of
impulsivity.
Interestingly,
differences
in
impulsivity
between
prenatally
cocaine‐exposed
and
control
monkeys
were
only
observed
in
the
conditioned
behavioral
measures.
The
two
unconditioned
behavioral
measures
are
tasks
that
are
typically
used
in
the
rodents
to
assess
impulsivity
and
have
been
shown
to
correlate
with
drug
use
(Hooks
et
al.
1991;
Klebar
et
al.
2001;
Piazza
et
al.
1989,
1990;
reviewed
in
Piazza
and
Le
Moal
1998).
It
is
possible
that
these
unconditioned
measures
are
not
sufficient
to
see
differences
in
impulsivity
in
nonhuman
primates
or
that
more
complex,
conditioned
behavioral
measures
are
necessary
to
unmask
the
subtle
differences
in
impulsivity
in
prenatally
cocaine‐exposed
monkeys.
136
In
future
studies,
we
will
be
able
to
establish
which
impulsivity
measures
correlate
with
stimulant
self‐administration
in
this
same
cohort
of
monkeys
to
determine
which
tasks
have
the
most
predictive
ability.
It
has
been
hypothesized
that
some
negative
effects
of
cocaine,
particularly
those
regulated
by
monoamine‐rich
areas
of
the
brain,
such
as
deficits
in
impulse
control
(Bandstra
et
al.
2007),
will
ultimately
lead
to
higher
rates
of
substance
dependence.
Therefore,
the
relationship
between
addiction
and
impulsivity
(Jentsch
and
Taylor
1999;
Bickel
and
Marsch
2001;
de
Wit
2010)
suggests
that
the
increased
impulsivity
observed
in
the
male
monkeys
exposed
to
cocaine
in
utero
may
predispose
them
to
drug
use.
The
female
prenatally
cocaine‐exposed
monkeys
did
not
differ
from
controls
on
overall
impulsivity
which
indicates
they
may
be
protected
from
this
potential
vulnerability
to
substance
abuse.
Since
we
observed
deficits
in
impulsivity
15
years
after
the
cocaine
exposure
in
utero,
it
is
likely
that
the
early
deficits
in
attention
and
impulse
control
seen
in
the
human
cohort
studies
at
ages
4,
6,
and
9
years
old
(Savage
et
al.
2005;
Linares
et
al.
2006;
Pulsifer
et
al.
2008)
may
be
associated
with
disturbances
in
inhibitory
control
in
adolescence
and
adulthood
that
could
contribute
to
an
increased
vulnerability
to
substance
abuse.
Taken
together,
the
present
results
provide
evidence
for
long‐term
neurobehavioral
consequences
of
prenatal
cocaine
exposure
on
impulse
control
and
a
neurobiological
correlate
for
the
increase
impulsivity
observed
in
male,
but
not
female,
subjects.
137
ACKNOWLEDGEMENTS
This
research
was
supported
by
National
Institute
on
Drug
Abuse
grants
R01
DA25120,
R37
DA10584
and
K31
DA024485.
The
authors
report
no
conflict
of
interest
and
would
like
to
acknowledge
the
excellent
technical
assistance
of
Tonya
Calhoun
and
Whitney
Wilson.
The
authors
also
thank
Dr.
William
L.
Woolverton
for
technical
consultation
and
Dr.
Merle
Paule
for
providing
information
related
to
the
histories
of
these
monkeys.
138
TABLE
1.
COMPARISON
OF
CSF
5‐HIAA
AND
HVA
(MEAN
±
SEM)
BETWEEN
MALE
AND
FEMALE
PRENATALLY
COCAINE‐EXPOSED
MONKEYS
AND
CONTROLS
5‐HIAA
(nM)
HVA
(nM)
Male
Prenatally
Cocaine
Exposed
148
±
18.1
614.7
±
68.5
Male
Controls
153.5
±
4.9
Female
Prenatally
Cocaine
Exposed
177.1
±
6.4
156.0
±
24.4
734.2
±
86.8
802.7
±
113.1
785.1
±
87.1
139
Female
Controls
TABLE
2.
RESPONSE
RATES
(RESP/SEC)
DURING
THE
DELAY
DISCOUNTING
TASK¶.
Delay
Value
(sec)
0
10§
30
60
120†
Prenatally
Cocaine
Exposed
Monkeys
Immediate
Delayed
reinforcer
key
reinforcer
key
1.85
±
0.39
1.93
±
0.29
1.30
±
0.35
1.11
±
0.28
1.53
±
0.48
1.32
±
0.35
1.84
±
0.43
1.61
±
0.40
1.36
±
0.29
1.60
±
0.35
Control
Monkeys
Immediate
reinforcer
key
1.27
±
0.39
1.08
±
0.43
0.96
±
0.27
1.19
±
0.29
1.38
±
0.25
Delayed
reinforcer
key
1.45
±
0.33
1.05
±
0.33
1.03
±
0.22
1.36
±
0.23
1.55
±
0.34
¶
All
points
are
means
(±
SEM)
of
10
monkeys,
except
where
noted
§
n=10
for
prenatal
cocaine
group
and
n=7
for
controls
†
n=
6
for
prenatal
cocaine
group
and
n=9
for
controls
140
FIGURE
1.
A:
Latency
to
touch
a
novel
object
placed
in
the
monkey’s
home
cage
(in
sec).
B:
Number
of
gridline
crossings
in
a
novel
environment
over
30
min.
Values
shown
are
mean
±
SEM
for
cocaine‐exposed
(filled
bars)
and
control
(open
bars)
male
and
female
monkeys.
141
FIGURE
2.
Number
of
sessions
to
extinguish
previously
food‐reinforced
responding
in
male
and
female
monkeys
prenatally
exposed
to
cocaine
(filled
bars)
and
controls
(open
bars).
Each
bar
represents
mean
±
SEM
values.
*p<0.05.
142
FIGURE
3.
Percentage
of
trials
in
which
the
larger,
delayed
reinforcer
was
chosen
over
the
smaller,
immediate
reinforcer
as
a
function
of
delay
value.
Data
are
from
representative
prenatally
cocaine
exposed
(left)
and
control
(right)
male
monkeys.
The
delay
value
at
which
the
curve
intersects
with
the
dashed
line
(50%
choice
of
larger
reinforcer)
represents
the
indifference
point.
143
FIGURE
4.
Mean
indifference
points
calculated
from
delay‐discounting
procedures
for
monkeys
prenatally
exposed
to
cocaine
(filled
bars)
and
controls
(open
bars).
Data
are
shown
from
male
(left)
and
female
(right)
monkeys.
Each
bar
represents
mean
±
SEM
values.
*p<0.05.
144
FIGURE
5.
Overall
impulsivity
rank
across
4
measures
of
impulsivity
(novel
object
reactivity,
locomotor
activity,
response
extinction
and
delay
discounting)
in
male
(left)
and
female
(right)
prenatally
cocaine
exposed
(filled
bars)
and
control
(open
bars)
monkeys.
To
calculate
the
score,
monkeys
were
ranked
from
1
(least
impulsive)
to
20
(most
impulsive)
and
an
overall
mean
was
determined
for
each
animal.
Higher
scores
represent
greater
impulsivity.
Bars
represent
mean
±
SEM
values.
*p<0.05.
145
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155
CHAPTER
IV
INCREASED
VULNERABILITY
TO
SELF­ADMINISTER
COCAINE
IN
ADULT
RHESUS
MONKEYS
EXPOSED
TO
COCAINE
THROUGHOUT
GESTATION
Lindsey
R.
Hamilton,
Michael
A.
Nader
The
following
manuscript
is
in
preparation
to
be
submitted
to
Science
in
May
2010.
Stylistic
variations
are
due
to
the
requirements
of
the
journal.
Lindsey
R.
Hamilton
performed
the
experiments,
analyzed
the
data,
and
prepared
the
manuscript.
Michael
A.
Nader
acted
in
an
advisory
and
editorial
capacity.
156
ABSTRACT
RATIONALE:
Prenatal
cocaine
exposure
has
been
associated
with
alterations
in
the
dopamine
(DA)
system
and
increased
impulsivity
in
adult
monkeys.
However,
whether
these
neurobiological
and
behavioral
outcomes
of
prenatal
cocaine
exposure
results
in
altered
sensitivity
to
the
reinforcing
effects
of
stimulants
in
nonhuman
primates
is
not
known.
OBJECTIVES:
To
assess
vulnerability
to
acquire
cocaine
self‐administration
in
15
year‐old
rhesus
monkeys
exposed
to
cocaine
or
saline
in
utero
(n=10
per
group).
MATERIALS
AND
METHODS:
Monkeys
were
trained
to
self‐administer
food
pellets
(1
g)
under
a
fixed‐ratio
(FR)
30
schedule
of
reinforcement.
Saline
and
ascending
doses
of
intravenous
cocaine
(0.001‐0.3
mg/kg/injection)
were
substituted
for
food
pellets.
Acquisition
of
cocaine
self‐administration
was
operationally
defined
as
the
lowest
dose
in
which
response
rates
were
signficantly
greater
than
saline‐contingent
rates
of
responding.
RESULTS:
Prenatally
cocaine‐exposed
monkeys
acquired
cocaine
self‐administration
at
lower
doses
than
controls
and
required
less
cocaine
history
prior
to
finding
a
dose
of
drug
reinforcing.
Vulnerability
to
self‐administer
cocaine
was
found
to
be
related
to
an
individual
phenotype
involving
increased
dopamine
D3
receptor
function
and
impulsivity.
CONCLUSIONS:
These
findings
suggest
that
prenatal
cocaine
exposure
results
in
increased
vulnerability
to
stimulant
self‐adminstration.
157
Keywords:
Prenatal
cocaine
–
Cocaine
–
Self­Administration
–
Predisposition
–
Acquisition
–
Rhesus
monkey
158
Although
rates
of
prenatal
cocaine
exposure
peaked
during
the
late
1980s
and
early
1990s,
it
continues
presently
with
approximately
50,000
additional
children
born
each
year
(National
Pregnancy
and
Health
Survey,
1996).
Widespread
use
of
cocaine
in
the
United
States
has
resulted
in
more
than
1
million
children
prenatally
exposed
to
cocaine,
many
of
whom
are
now
entering
adolescence
or
young
adulthood,
a
time
when
many
experiment
with
drugs
of
abuse.
For
example,
approximately
1
in
5
Americans
between
the
ages
of
21‐25
have
tried
cocaine
at
least
once
in
their
lifetime
(SAMHSA,
2008).
Children
and
young
adults
that
were
exposed
to
cocaine
in
utero
may
be
sensitized
to
the
reinforcing
effects
of
cocaine
and
be
more
vulnerable
to
progressing
to
drug
abuse.
Currently,
the
human
cohort
studies
have
only
followed
the
prenatally
cocaine‐exposed
children
and
non‐
exposed
controls
through
13
years
old.
It
is
not
yet
known
whether
prenatal
cocaine
exposure
is
associated
with
increased
risk
of
substance
dependence.
There
is
accumulating
evidence
that
prenatal
exposure
to
substances
predicts
subsequent
substance
use
later
in
life.
An
elevated
risk
of
tobacco
dependence
and
early
adolescent
smoking
and
tobacco
smoking
has
been
found
in
offspring
of
mothers
who
smoked
during
their
pregnancy
(Kandel
et
al.,
1994;
Buka
et
al.,
2003;
Cornelius
et
al.,
2005).
Similarly,
prenatal
marijuana
exposure
has
been
associated
with
initiation
and
use
of
marijuana
among
young
adults
(Porath
and
Fried,
2005).
A
prospective,
longitudinal
study
observed
a
significant
correlation
between
prenatal
alcohol
exposure
and
subsequent
alcohol
use
and
alcohol
problems
at
14
years
(Baer
et
al.,
159
1998)
and
at
21
years
old
(Baer
et
al.,
2003),
even
after
controlling
for
family
history
of
alcohol
abuse.
While
no
human
studies
have
examined
the
effect
of
prenatal
cocaine
exposure
and
vulnerability
to
substance
abuse,
studies
in
rodents
suggest
that
the
reinforcing
efficacy
of
stimulants
is
altered
by
gestational
cocaine
exposure.
Prenatal
cocaine
exposure
enhances
the
cocaine‐induced
potentiation
of
brain
stimulation
reward
(Lin
and
Kellogg,
1996;
Malanga
et
al.,
2008).
Prenatally
cocaine
exposed
rats
also
showed
significantly
higher
rates
of
responding
compared
to
controls
for
a
low
dose
of
cocaine
available
under
an
FR
1
schedule
of
reinforcement
(Keller
et
al.,
1996).
Additionally,
Rocha
et
al.
(2002)
found
that
mice
exposed
to
cocaine
in
utero
acquired
cocaine
self‐administration
more
readily
than
controls
despite
observing
no
differences
in
rate
of
acquisition
of
food‐reinforced
responding.
However,
there
are
conflicting
reports
about
prenatally
cocaine
exposed
animals’
propensity
to
be
more
sensitive
to
the
reinforcing
effects
of
cocaine.
Heyser
et
al.
(1992)
found
that
rats
exposed
to
cocaine
throughout
gestation
did
not
acquire
cocaine
conditioned
place
preference
which
suggests
a
reduction
in
cocaine
reward.
Furthermore,
Hecht
et
al.
(1998)
determined
that
prenatally
cocaine‐exposed
rats
were
less
sensitive
to
the
reinforcing
strength
of
cocaine
because
these
animals
had
signficantly
lower
break
points
for
cocaine
using
a
progressive‐ratio
schedule
of
reinforcement.
Therefore,
it
has
not
been
well
established
whether
prenatal
cocaine
exposure
alters
vulnerability
to
cocaine
self‐administration.
160
In
order
to
evaluate
the
consequences
of
in
utero
drug
exposure
in
adulthood,
the
present
study
examined
prenatal
cocaine
exposure
in
rhesus
moneys.
These
animals
had
been
exposed
to
cocaine
or
saline
throughout
the
25
weeks
of
gestation
(Morris
et
al.,
1996)
and
were
studied
as
adults
(14‐15
years
old).
We
recently
examined
dopamine
(DA)
receptor
function
in
these
adult
monkeys
(Hamilton
et
al.,
2010)
using
agonist‐elicited
behaviors
and
PET
imaging.
There
were
no
differences
in
DA
D1
and
D2
receptor
function,
but
prenatally
cocaine‐exposed
animals
were
more
sensitive
to
the
behavioral
effects
of
the
D3
agonist
quinpirole
compared
to
controls.
Additionally,
we
have
previously
found
that
male,
but
not
female,
prenatally
cocaine‐exposed
monkeys
are
more
impulsive
than
controls
(Hamilton
et
al.,
submitted).
Long‐lasting
alterations
in
the
dopaminergic
system
and
increased
behavioral
impulsivity
are
risk
factors
for
increased
vulnerability
to
self‐administer
stimulants,
suggesting
that
prenatally
cocaine‐exposed
monkeys
may
be
more
sensitive
to
the
reinforcing
effects
of
cocaine
as
adults.
In
the
present
study,
we
extended
the
behavioral
assessment
of
this
cohort
to
examine
acquisition
of
cocaine
self‐administration.
METHODS
SUBJECTS.
Nineteen
adult
rhesus
monkeys
(Macaca
mulatta),
born
between
1993
and
1995
and
raised
at
the
FDA
facility
in
Little
Rock,
AR
until
their
arrival
at
Wake
Forest
University
in
2007,
served
as
subjects.
Ten
monkeys
(6
male,
4
female)
were
prenatally
exposed
to
cocaine
and
9
monkeys
(5
161
male,
4
female)
served
as
controls,
as
described
previously
(Morris
et
al.,
1997).
Briefly,
the
mothers
of
the
monkeys
used
in
this
study
received
intramuscular
injections
escalating
doses
of
cocaine
three
times
per
day
for
the
entire
course
of
gestation
(Morris
et
al.,
1996).
The
mean
gestational
cocaine
exposure
was
1131.5
mg/kg.
Other
than
their
prenatal
drug
histories,
all
monkeys
had
identical
experimental
histories
(see
Paule
et
al.,
1996;
Morris
et
al.,
1996).
Monkeys
were
individually
housed
in
stainless‐
steel
cages
with
water
available
ad
libitum
and
had
visual
and
auditory
contact
with
each
other.
Since
we
have
previously
shown
that
monoamine
function
is
influenced
by
menstrual
cycle
(Czoty
et
al.
2009),
we
monitored
menstrual
cycle
phase
throughout
the
experiment
by
daily
vaginal
swabs.
Days
of
bleeding
were
recorded
as
indicative
of
menses.
During
quarantine,
a
free‐feeding
weight
was
determined
and
monkeys’
body
weights
were
maintained
at
approximately
95%
of
that
value
throughout
these
studies
(LabDiet
Monkey
Chow
and
fresh
fruit).
Each
monkey
was
fitted
with
an
aluminum
collar
(Primate
Products,
Redwood
City,
CA)
and
trained
to
sit
calmly
in
a
standard
primate
chair
(Primate
Products)
using
a
specially
designed
stainless‐steel
pole
that
attached
to
the
collar.
All
manipulations
were
performed
in
accordance
with
the
2003
National
Research
Council
Guidelines
for
the
Care
and
Use
of
Mammals
in
Neuroscience
and
Behavioral
Research
and
were
approved
by
the
Wake
Forest
University
Institutional
Animal
Care
and
Use
Committee.
162
APPARATUS.
The
apparatus
consisted
of
a
ventilated,
sound‐attenuating
chamber
(1.5
x
0.74
x
0.76
m;
Med
Associates,
East
Fairfield,
VT)
designed
to
accommodate
a
primate
chair.
Two
response
keys
(5
cm
wide)
were
located
on
one
side
of
the
chamber
with
a
horizontal
row
of
three
stimulus
lights
14
cm
above
each
response
key
and
a
food
receptacle
was
located
between
the
response
keys.
The
receptacle
was
connected
with
tygon
tubing
to
a
pellet
dispenser
(Gerbarands
Corp.,
Arlington,
MA)
located
on
the
top
of
the
chamber
for
delivery
of
1‐g
banana‐flavored
food
pellets
(P.K.
Noyes
Co.,
Lancaster,
NH).
An
infusion
pump
(Cole‐Palmer,
Inc.,
Chicago,
IL)
was
located
on
the
top
of
the
chamber.
SURGERY.
Each
monkey
was
prepared
with
a
chronic
indwelling
venous
catheter
and
subcutaneous
vascular
port
(Access
Technologies,
Skokie,
IL)
under
sterile
surgical
conditions.
Anesthesia
was
induced
and
maintained
with
ketamine
(15
mg/kg)
and
butorphanol
(0.025
mg/kg).
Vital
signs
were
monitored
for
the
duration
of
the
surgery.
Briefly,
a
catheter
was
inserted
into
the
femoral
vein
to
the
level
of
the
vena
cava.
The
distal
end
of
the
catheter
was
passed
subcutaneously
to
a
point
slightly
off
the
midline
of
the
back,
where
an
incision
was
made.
The
end
of
the
catheter
was
then
attached
to
the
vascular
access
port
and
placed
in
a
pocket
formed
by
blunt
dissection.
Each
port
and
catheter
was
filled
with
heparinized
saline
solution
(100
Units/ml)
after
every
experimental
session
to
prolong
the
patency.
Prior
to
each
drug
self‐administration
session,
the
back
of
the
animal
was
cleaned
163
with
betadine
and
95%
EtOH
and
the
port
was
connected
to
the
infusion
pump
located
outside
the
chamber
via
a
20‐gauge
Huber
Point
Needle
(Access
Technologies).
The
pump
was
operated
for
approximately
3
sec
to
fill
the
port
and
catheter
line
with
drug
prior
to
starting
the
session.
ACQUISITION
OF
COCAINE
SELF­ADMINISTRATION.
Monkeys
were
initially
trained
to
respond
on
the
left
and
right
keys
by
reinforcing
each
response
with
a
1‐g
banana‐flavored
pellet;
a
30‐sec
timeout
followed
each
food
presentation.
The
light
above
the
response
key
signaled
food
availability;
only
one
key
was
active
during
a
session.
Over
the
course
of
2‐3
weeks,
the
number
of
responses
required
was
increased
until
a
fixed‐ratio
(FR)
30
schedule
of
food
presentation
was
achieved.
Sessions
ended
after
30
reinforcers
had
been
delivered
or
60
min
had
elapsed.
When
responding
was
reliably
maintained
(i.e.,
mean
response
rate
±
20%
for
3
consecutive
sessions)
on
both
keys
and
maximal
food
reinforcement
was
obtained
consistently,
intravenous
catheters
were
implanted.
After
implantation
of
the
catheter,
baseline
food
reinforcement
response
rates
were
re‐established
over
5
sessions,
but
only
on
the
response
key
associated
with
the
highest
rates.
For
control
monkeys,
4
had
higher
response
rates
on
the
left
key
and
6
on
the
right
key
and
for
prenatal
cocaine
exposed
monkeys
the
distribution
was
3
on
the
left
key
and
7
on
the
right
key.
Saline
injections
were
substituted
for
food
pellets
for
at
least
5
164
consecutive
sessions
and
until
responding
was
deemed
extinguished.
The
criteria
for
extinguishing
food‐reinforced
responding
were
3
consecutive
sessions
in
which
response
rates
were
reduced
by
at
least
80%
of
baseline
food
reinforced
responding
(i.e.,
mean
response
rate
±
20%
for
3
consecutive
sessions)
with
no
trends
in
responding.
The
primary
dependent
measure
was
the
number
of
sessions
to
meet
these
criteria.
Next,
baseline
food‐maintained
rates
of
responding
were
re‐
established.
Injections
of
cocaine
HCl
(National
Institute
on
Drug
Abuse,
Bethesda,
MD,
dissolved
in
sterile
0.9%
saline)
were
than
substituted
for
the
food
pellets
in
ascending
order
from
0.001
mg/kg/injection
increasing
in
half
log
units
to
0.3
mg/kg/injection.
Drug
doses
were
available
for
at
least
5
consecutive
sessions
until
animals
reached
criteria
for
stability
(response
rate
mean
±20%
with
no
trends
for
3
consecutive
sessions).
In
between
drug
doses,
monkeys
returned
to
a
food‐reinforced
baseline
for
at
least
3
consecutive
sessions.
The
dose
at
which
cocaine
self‐administration
was
determined
to
be
acquired
was
the
first
dose
at
which
response
rate
was
signficantly
greater
than
the
response
rate
when
saline
was
available
(see
Data
Analysis).
For
female
subjects,
drug
was
only
made
available
during
the
follicular
phase
of
the
menstrual
cycle
(days
2‐12
where
day
1
is
the
first
day
of
menses).
During
the
luteal
phase,
female
subjects
responded
under
an
FR
30
schedule
of
food
presentation.
165
DATA
ANALYSIS.
A
t‐test
was
used
to
determine
if
response
rates
under
each
dose
of
cocaine
was
greater
than
saline‐contingent
response
rates.
To
determine
if
there
were
differences
in
the
rate
of
acquisition
between
prenatally
cocaine
exposed
and
control
animals,
a
logrank
analysis
of
Kaplan‐
Meier
survival
curves
was
computed.
Additionally,
a
t‐test
was
used
to
compare
the
cumulative
exposure
to
cocaine
prior
to
acquisition
between
the
two
groups.
After
the
individual
animals
were
classified
into
high
or
low
vulnerability
groups,
t‐tests
and
Mann‐Whitney
tests
were
used
to
compare
the
two
groups
for
differences.
In
all
cases,
significance
was
accepted
at
the
95%
level
of
confidence
(p
<
0.05).
RESULTS
Acquisition
of
food‐maintained
responding
on
an
FR
30
schedule
did
not
differ
between
the
two
groups
(sessions
to
acquire
food‐maintained
FR
30
was
34.5
±
4.4
for
the
prenatally
cocaine
exposed
animals
and
35.5
±
5.9
for
the
controls).
Mean
response
rates
under
the
FR
30
schedule
of
food
presentation
were
not
different
in
male
monkeys
with
mean
(±
SEM)
values
of
3.89
(±
0.68)
and
2.46
(±
0.54)
resp/sec
for
control
and
prenatally
cocaine‐
exposed
monkeys,
respectively.
Similarly,
female
monkeys
did
not
differ
in
mean
response
rates
between
groups
(1.60
±
0.30
and
2.64
±
1.16
resp/sec,
for
control
and
prenatally
cocaine‐exposed
monkeys,
respectively).
Neither
prenatally
cocaine‐exposed
or
control
monkeys
differed
in
mean
response
166
when
saline
was
available
(Males:
0.03
±
0.01
and
0.04
±
0.02,
respectively;
Females:
0.02
±
0.01
and
0.02
±
0.01,
respectively).
After
testing
all
cocaine
doses
(0.001‐0.3
mg/kg/injection)
once,
80%
(8
of
10)
of
prenatally
cocaine
exposed
monkeys
acquired
cocaine
self‐
administration
compared
to
only
55%
(5
of
9)
of
controls
(Fig.
1).
The
remaining
2
prenatally
cocaine
exposed
monkeys
and
3
of
the
4
remaining
control
monkeys
eventually
acquired
cocaine
self‐administration
once
the
doses
were
tested
a
second
time.
One
female
control
monkey
never
found
any
dose
of
cocaine
reinforcing.
A
logrank
test
of
Kaplan‐Meier
survival
curves
revealed
no
differences
between
prenatally
cocaine‐exposed
and
control
monkeys
on
the
rate
of
acquisition
of
cocaine
self‐administration
(χ2
=
1.34,
p
=
0.25).
The
median
acquisition
dose
(the
dose
by
which
50%
of
the
animals
had
acquired
self‐administration)
was
0.01
mg/kg
for
the
prenatally
cocaine
exposed
animals
and
0.3
mg/kg
for
the
control
animals.
A
t‐test
revealed
greater
cumulative
cocaine
exposure
since
beginning
the
experiment
until
acquisition
of
cocaine
self‐adminstration
in
controls
compared
to
prenatally
cocaine‐exposed
monkeys
(p
=
0.04)
(Fig.
2).
Based
on
each
animal’s
individual
cumulative
intake
of
cocaine
prior
to
acquisition,
animals
were
split
into
two
groups:
high
vulnerability
(HV,
cumulative
cocaine
intake
prior
to
acquisition
<
3
mg/kg,
n
=
10)
and
low
vulnerability
(LV,
cumulative
cocaine
intake
prior
to
acquisition
>
3
mg/kg,
n
=
9)
(Fig.
3).
A
t‐test
showed
that
the
number
of
self‐administration
sessions
to
reach
acquisition
criteria
was
signficantly
greater
in
the
LV
group
(40.8
±
167
6.0
sessions)
compared
to
the
HV
group
(15.4
±
2.5
sessions)
(p
=
0.0008)
(data
not
shown).
Using
data
generated
from
these
monkeys
in
earlier
studies
(Hamilton
et
al.,
2010,
under
review),
a
Mann‐Whitney
test
revealed
that
the
HV
group
were
more
impulsive
compared
to
the
LV
(p
=
0.04)
(Fig.
4,
panel
A)
and
a
t‐test
revealed
the
HV
group
had
greater
frequency
of
yawns
elicited
by
quinpirole
(p
=
0.03)
(Fig.
4,
panel
B)
compared
to
the
LV
group.
Additionally,
there
was
significant
correlation
between
quinpirole‐elicited
yawning
and
cumulative
cocaine
intake
prior
to
acquisition
(r2
=
0.18,
p
=
0.05)
(Fig.
4,
panel
C).
There
was
no
difference
observed
between
the
HV
and
LV
groups
for
any
other
phenotypic
variable
examined
including
D2
receptor
availability,
D1
receptor‐elicited
eye‐blinking,
or
5‐HIAA
or
HVA
basal
cerebrospinal
fluid
concentration
(data
not
shown).
DISCUSSION
The
purpose
of
the
present
studies
was
to
determine
whether
prenatally
cocaine
exposed
adult
rhesus
monkeys
were
more
vulnerable
to
stimulant
self‐administration
compared
to
controls.
To
study
vulnerability,
monkeys
responded
under
an
FR
30
schedule
of
food
presentation
and,
when
stable,
saline
and
then
increasing
cocaine
doses
were
examined.
Between
saline
or
various
cocaine
doses,
responding
was
again
maintained
by
food.
In
this
way,
acquisition
of
cocaine
reinforcement
could
be
operationally
defined
as
the
lowest
dose
in
which
cocaine‐maintained
responding
was
significantly
168
higher
than
saline‐contingent
responding
(i.e.,
the
lowest
dose
in
which
cocaine
functioned
as
a
reinforcer).
Prenatally
cocaine‐exposed
monkeys
acquired
cocaine
reinforcement
at
lower
doses
than
control
animals.
This
is
not
simply
a
difference
in
learning
to
acquire
because
acquisition
of
food‐
maintained
responding
on
an
FR
30
schedule
did
not
differ
between
the
two
groups.
Furthermore,
the
cumulative
cocaine
dose
prior
to
acquisition
(i.e.,
the
amount
of
cocaine
that
had
been
self‐administered
prior
to
a
dose
functioning
as
a
reinforcer)
was
significantly
lower
for
prenatal
cocaine
exposed
monkeys
compared
to
controls.
This
is
of
relevance
because
cocaine
will
function
as
a
reinforcer
in
all
monkeys;
however,
compared
to
controls,
the
amount
of
cocaine
history
necessary
for
the
prenatally
cocaine‐exposed
monkeys
is
substantially
less
than
the
amount
necessary
for
control
monkeys,
suggesting
they
are
more
sensitive
to
the
reinforcing
effects
of
cocaine
than
controls.
After
completing
cocaine
dose‐response
curves
for
all
animals,
several
phenotypic
variables
that
have
been
thought
to
be
related
to
cocaine
self‐
administration
were
examined.
To
do
this,
individual
monkeys
were
characterized
as
highly
vulnerable
(HV)
or
low
vulnerable
(LV)
to
cocaine
reinforcement
based
on
the
amount
of
cocaine
intake
prior
to
acquisition
(i.e.,
the
10
monkeys
with
the
lowest
intakes
were
considered
HV,
while
the
9
with
the
highest
intakes
were
considered
LV).
Of
the
10
HV
monkeys,
70%
were
prenatally
cocaine
exposed.
We
previously
reported
that
there
were
no
group
or
sex
differences
in
DA
D2‐like
receptor
function
using
PET
imaging
169
in
this
cohort
(Hamilton
et
al.,
2010).
Other
pharmacological
studies
revealed
no
differences
in
D1‐like
receptor
function,
but
significant
differences
related
to
prenatal
drug
exposure
and
sensitivity
to
DA
D3
agonist
effects
in
male
monkeys
(Hamilton
et
al.,
2010).
Comparing
results
from
that
study
and
the
present
data,
we
determined
that
there
were
no
significant
differences
in
D2‐
like
receptor
availability
or
D1‐elicited
eye‐blinking
between
the
HV
and
LV
monkeys.
However,
the
HV
monkeys
previously
displayed
increased
frequency
of
yawns
elicited
by
quinpirole
compared
to
LV
monkeys
and
there
was
a
significant
correlation
between
peak
yawns
and
the
cumulative
cocaine
intake
prior
to
acquisition,
suggesting
a
role
for
D3
receptor
function
in
cocaine
reinforcement.
We
also
compared
the
results
from
the
present
study
to
impulsivity
measures
previously
examined.
The
prenatally
cocaine
exposed
monkeys
were
more
impulsive
compared
to
controls
(Hamilton
et
al.,
under
review).
As
it
relates
to
self‐administration,
HV
monkeys
are
more
impulsive
across
multiple
measures
of
impulsivity
compared
to
LV
monkeys,
which
suggests
that
impulsivity
is
a
behavioral
phenotype
that
predicts
acquisition
of
stimulant
self‐administration.
By
using
a
within
subject
design
and
several
behavioral
and
neuropharmacological
measures,
we
were
able
to
identify
a
specific
profile
or
phenotype
that
predicted
vulnerability
to
stimulant
self‐administration.
Increased
D3
receptor
function
appears
to
be
a
neurobiological
risk
factor
that
predisposes
individuals
to
cocaine
self‐administration.
The
present
findings
are
consistent
with
other
studies
showing
an
association
between
170
low
striatal
D2/D3
receptor
availability
and
impulsivity
in
human
methamphetamine‐dependent
subjects
(Lee
et
al.,
2009)
and
in
rodents
(Dalley
et
al.,
2007).
Additionally,
an
upregulation
of
D3
receptors
has
been
observed
in
individuals
that
died
from
a
cocaine
overdose
(Staley
and
Mash,
1996),
which
indicates
perhaps
D3
function
plays
a
critical
role
in
the
reinforcing
effects
of
cocaine.
The
present
findings
also
provide
supporting
evidence
for
the
D3
receptor
being
a
promising
pharmacological
target
for
treating
impulsivity‐related
disorders,
including
substance
abuse
(for
reviews
see
Le
Foll
et
al.,
2005;
Sokoloff
et
al.,
2006;
Heidbreder,
2008).
Our
findings
that
increased
impulsivity
appears
to
be
a
behavioral
risk
factor
for
vulnerability
to
self‐administer
cocaine
support
the
relationship
between
addiction
and
impulsivity
that
has
been
previously
reported
in
the
literature
(Jentsch
and
Taylor,
1999;
Bickel
and
Marsch,
2001;
De
Wit,
2010).
In
this
study,
only
68%
(13
out
of
19)
of
the
subjects
acquired
cocaine
self‐administration
initially,
which
is
very
low
in
contrast
to
our
laboratory’s
typical
acquisition
rate
of
approximately
100%.
However,
this
lower
acquisition
rate
may
be
related
to
the
experimental
design
and
is
a
strength
of
the
acquisition
procedure.
Typically,
to
have
a
monkey
acquire
cocaine
self‐administration,
subjects
are
trained
to
respond
on
an
operant
schedule
with
food
reinforcement
and
an
intermediate
dose
of
cocaine
(0.03
mg/kg/injection)
is
made
available,
which
results
in
almost
every
subject
acquiring
self‐administration
very
quickly.
In
the
present
study,
we
started
with
an
extremely
low
cocaine
dose
(0.001
mg/kg/injection),
made
many
171
doses
available
in
an
ascending
order,
and
repeatedly
went
back
to
a
food
baseline
between
every
dose
available.
This
design
resulted
in
repeated
pairings
of
the
cues
such
as
the
pump
noise
and
lights
changing
associated
with
receiving
an
injection
and
very
low
doses
of
drug
that
were
not
reinforcing,
which
is
the
equivalent
of
repeatedly
extinguishing
responding
in
these
subjects.
Ultimately
95%
(18
of
19)
of
the
subjects
in
this
cohort
acquired
self‐administration,
although
the
median
dose
for
control
monkeys
was
one
log‐unti
higher
than
the
typical
0.03
cocaine
dose
we
use
for
training.
The
experimental
design
provided
a
more
sensitive
measure
of
cocaine
acquisition
and
one
that
allowed
us
to
determine
individual
differences
in
vulnerability
for
cocaine
to
function
as
a
reinforcer.
Individual
differences
in
vulnerability
to
addiction
is
well
accepted
in
the
clinical
literature
but
has
not
been
thoroughly
investigated
in
animal
self‐
administration
studies.
When
studying
the
etiology
of
drug
addiction,
an
important
question
is
why
certain
individuals
report
becoming
addicted
to
a
substance
after
their
first
dose
whereas
other
individuals
are
able
to
use
a
drug
for
months
or
even
years
only
sporadically
before
becoming
addicted
to
the
substance
(O’Brien
et
al.,
1986).
The
present
findings
suggest
that
a
particular
set
of
traits,
increased
impulsivity
and
increased
D3
receptor
function,
can
predict
individual
differences
in
the
development
of
cocaine
self‐administration
in
monkeys.
The
differences
we
observed
in
impulsivity
measures,
D3
receptor
function,
and
predisposition
to
acquire
stimulant
self‐administration
were
15
172
years
after
the
cocaine
exposure
in
utero.
Our
data
suggest
that
prenatal
cocaine
exposure
may
increase
the
likelihood
of
an
adult
behavioral
and
neurobiological
phenotype
that
predisposes
individuals
to
substance
abuse.
This
is
supported
by
the
human
prospective
longitudinal
studies
which
have
found
early
deficits
in
attention
and
impulse
control
in
prenatally
cocaine
exposed
children
at
ages
4,
6,
and
9
years
old
(Savage
et
al.,
2005;
Linares
et
al.,
2006;
Pulsifer
et
al.,
2008),
indicating
that
these
children
may
also
be
more
vulnerable
to
substance
abuse.
Taken
together,
the
present
results
provide
supporting
evidence
for
long‐term
neurobehavioral
consequences
of
prenatal
cocaine
exposure
on
vulnerability
to
self‐administer
cocaine.
ACKNOWLEDGEMENTS
This
research
was
supported
by
National
Institute
on
Drug
Abuse
grants
R01
DA25120,
R37
DA10584
and
K31
DA024485.
The
authors
report
no
conflict
of
interest
and
would
like
to
acknowledge
the
excellent
technical
assistance
of
Tonya
Calhoun
and
Whitney
Wilson.
The
authors
also
thank
Dr.
Merle
Paule
for
providing
information
related
to
the
histories
of
these
monkeys
and
Dr.
Beth
Reboussin
for
her
assistance
with
statistical
analysis.
173
FIGURE
1.
Percentage
of
prenatally
cocaine
exposed
(closed
symbols)
and
control
(open
symbols)
monkeys
that
reached
criteria
to
acquire
cocaine
self‐
administration
at
various
doses
of
cocaine
available
under
an
FR
30
schedule
of
reinforcement.
174
FIGURE
2.
Amount
of
cocaine
intake
prior
to
reaching
criteria
to
acquire
cocaine
self‐administration
in
prenatally
cocaine
exposed
and
control
monkeys.
Bars
represent
mean
±
SEM
values.
*p<0.05.
175
FIGURE
3.
Amount
of
cocaine
intake
prior
to
reaching
criteria
to
acquire
cocaine
self‐administration
in
high
vulnerable
and
low
vulnerable
monkeys.
Bars
represent
mean
±
SEM
values.
*p<0.05.
176
177
FIGURE
4.
a)
Impulsivity
score
derived
from
4
behavioral
measures
of
impulsivity
(1
=
least
impulsive,
20
=
most
impulsive)
in
high
and
low
vulnerable
monkeys
as
described
in
Hamilton
et
al.,
(under
review).
Squares
represent
prenatally
cocaine
exposed
monkeys
and
triangles
represent
control
monkeys.
b)
Peak
yawns
elicited
by
the
D3
receptor
agonist
quinpirole
in
high
and
low
vulnerable
monkeys.
Squares
represent
prenatally
cocaine
exposed
monkeys
and
triangles
represent
control
monkeys.
Quinpirole‐elicited
yawning
data
are
from
Hamilton
et
al.
(2010).
c)
Relationship
between
peak
yawns
elicited
by
quinpirole
and
cumulative
cocaine
intake
prior
to
reaching
acquisition
criteria.
178
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181
CHAPTER
V
DISCUSSION
“Some
addicts
go
for
months
or
years
using
heroin
or
cocaine
only
on
weekends
before
becoming
a
daily
(addicted)
user.
Others
report
that
they
had
such
an
intense
positive
response
that
they
became
addicted
with
the
first
dose…”
O’Brien
et
al.,
1986.
Studying
a
complex,
multi‐dimensional
psychiatric
disorder
like
substance
abuse
is
made
even
more
challenging
by
the
fact
that
drug
abusers
are
a
highly
heterogenous
group.
Determining
individual
vulnerability
to
go
from
misuse
of
drugs
to
addiction,
as
the
O’Brien
and
colleagues
quote
indicates,
is
a
critical
line
of
research
in
the
study
of
the
etiology
of
drug
addiction.
It
is
believed
that
there
are
multiple
factors
that
contribute
to
vulnerability,
inherent
or
acquired
(Le
Moal,
2009).
Quantitative
traits
that
indicate
a
specific
risk
factor
can
be
conceptualized
as
a
behavioral
or
biological
phenotype.
The
research
in
this
dissertation
was
designed
to
examine
several
of
the
multiple
determinants
of
an
addiction
phenotype
and
their
interactions.
These
studies
attempted
to
try
to
elucidate
a
vulnerable
phenotype
in
order
to
identify
characteristics
(behavioral
and
neuropharmacological)
that
may
predispose
an
individual
to
addiction
by
characterizing
the
long‐term
effects
of
prenatal
cocaine
exposure
in
adult
182
rhesus
monkeys.
The
dopamine
receptor
system,
behavioral
measures
of
impulsivity,
and
acquisition
of
cocaine
self‐administration
were
examined
in
a
cohort
of
adult
rhesus
monkeys
that
were
exposed
to
cocaine
throughout
gestation.
As
will
be
described
in
this
Chapter,
there
appears
to
be
a
relationship
between
DA
D3
receptor
function,
impulsivity,
and
acquisition
of
cocaine
self‐administration.
The
research
described
in
this
dissertation
supports
the
idea
that
there
are
biological
and
behavioral
phenotypes
that
seem
to
predispose
individuals
to
drug‐taking
behavior
and
that
prenatal
cocaine
exposure
can
increase
the
likelihood
of
these
phenotypes.
ACQUISITION
OF
COCAINE
SELF­ADMINISTRATION
Measuring
acquisition
of
drug
self‐administration
is
a
method
of
examining
the
etiology
of
drug‐taking
behavior
that
allows
for
the
investigation
of
variables
that
may
attenuate
or
enhance
initiation
of
drug
use.
Factors
that
impede
acquisition
may
be
targets
for
treatment.
Likewise,
variables
that
increase
the
rate
of
acquisition
may
be
identified
as
risk
factors
that
predispose
to
drug
use.
In
typical
acquisition
studies,
the
dose
of
the
drug
is
held
contant
and
the
criteria
to
reach
acquisition
are
defined
as
a
set
number
of
injections
received
or
set
amount
of
drug
taken
(mg/kg).
By
defining
acquisition
as
reaching
set
arbitrary
criteria,
it
can
be
argued
that
these
studies
are
assessing
criterion
performance
not
acquisition
of
the
drug
becoming
a
reinforcer.
For
example,
Carroll
and
Lac
(1997)
investigated
acquisition
of
amphetamine
(0.06
mg/kg/injection)
self‐administration
and
183
defined
acquisition
as
greater
than
50
injections
per
session.
One
rat
that
did
not
reach
this
acquisition
criterion
had
a
mean
of
44
injections
per
session
over
the
30
days
of
acquisition.
It
is
not
clear
whether
amphetamine
was
a
reinforcer
in
this
particular
rat
because
there
was
no
comparison
to
vehicle.
It
is
possible
that
amphetamine
was
a
reinforcer
in
this
animal
without
reaching
the
defined
arbitrary
criteria.
In
Chapter
IV,
an
acquisition
procedure
was
used
that
operationally
defined
acquisition
regardless
of
dose.
We
assessed
multiple
doses
of
cocaine
in
ascending
order
and
defined
acquisition
as
greater
responding
for
cocaine
than
when
saline
was
available
(Figure
1).
Each
animal’s
individual
saline
baseline
rates
of
responding
were
used
to
determine
whether
or
not
the
acquisition
criterion
had
been
met.
This
methodology
allowed
us
to
focus
on
individual
differences
in
acquiring
cocaine
reinforcement.
This
method,
which
used
very
low
doses
of
drug,
also
highlights
more
variability
between
subjects
than
training
an
animal
to
acquire
cocaine
self‐administration
at
a
moderate
or
high
dose.
This
increased
variability
allowed
the
groups
of
animals
to
differentiate
from
each
other
more
and
enhanced
our
ability
to
detect
variables
that
affected
acquisition
rate.
184
FIGURE
1.
Representative
response
rates
for
food
(open
symbols)
and
drug
(closed
symbols)
under
an
FR
30
schedule
of
reinforcement
during
the
acquisition
of
cocaine
self‐administration
for
a
prenatally
cocaine
exposed
monkeys.
The
lower
acquisition
rate
observed
in
these
studies
could
be
explained
by
latent
inhibition,
which
is
a
reduction
in
conditioning
to
a
stimulus
that
occurs
as
a
result
of
preexposure
to
that
stimulus
without
reinforcement
(Weiner
1990).
Since
the
acquisition
procedure
repeatedly
paired
doses
of
cocaine
that
were
not
reinforcing
to
the
animal
with
the
cues,
the
monkeys
may
have
learned
to
ignore
stimuli
that
are
repeatedly
presented
because
they
were
not
previously
followed
by
a
meaningful
consequence.
It
is
possible
that
the
latent
inhibition
processes
were
stronger
185
in
control
animals
compared
to
prenatally
cocaine‐exposed
animals
since
they
took
longer
to
acquire
cocaine
self‐administration.
The
prenatally
cocaine‐exposed
monkeys
may
be
less
responsive
to
Pavlovian
conditioning
compared
to
the
controls.
Latent
inhibition
is
a
robust
behavioral
phenomenon
and
can
be
demonstrated
in
many
species,
including
in
humans,
across
a
variety
of
classical
and
instrumental
conditioning
procedures,
including
avoidance,
taste
aversion,
and
discrimination
learning
(Lubow,
1989).
It
is
thought
that
latent
inhibition,
since
it
is
conserved
across
many
species
and
is
observed
across
a
broad
range
of
conditions,
serves
an
important
adaptive
function,
allowing
for
more
efficient
and
rapid
learning
(Lubow,
1989).
Additionally,
latent
inhibition
is
considered
to
reflect
animals’
learning
not
to
attend
to
or
to
ignore
irrelevant
stimuli
and
has
a
large
attentional
component.
Therefore,
in
addition
to
displaying
increased
sensitivity
to
the
reinforcing
effects
of
low
doses
of
cocaine,
prenatally
cocaine‐exposed
monkeys
may
also
be
demonstrating
altered
attentional
processes
compared
to
control
monkeys.
Since
it
has
been
hypothesized
that
activation
of
the
mesolimbic
dopaminergic
system
disrupts
the
latent
inhibition
processes
(Wiener,
1990)
and
prenatally
cocaine‐exposed
monkeys
have
increased
D3
receptor
function
(Hamilton
et
al.,
2010),
it
is
possible
that
the
prenatally
cocaine‐
exposed
monkeys
acquired
cocaine
self‐administration
more
readily
than
controls
due
to
alterations
in
their
latent
inhibition
processes.
186
This
explanation
is
supported
by
the
preliminary
data
indicating
that
when
the
cocaine
dose‐response
curves
are
re‐established
after
acquisition
has
already
occurred,
there
are
no
differences
between
prenatally
cocaine‐
exposed
monkeys
and
control
monkeys
(Figure
2).
This
would
be
consistent
with
the
human
studies
that
have
found
a
pattern
of
difficulties
with
sustained
and
selective
attention
(Bandstra
et
al.,
2001;
Savage
et
al.,
2005;
Linares
et
al.,
2006).
FIGURE
2.
Dose‐response
curves
for
prenatally
cocaine‐exposed
(closed
symbols)
and
control
(open
symbols)
monkeys
under
an
FR
30
schedule
of
reinforcement
during
the
acquisition
(left
panel)
and
maintenance
(right
panel)
of
cocaine
self‐administration.
The
prenatally
cocaine‐exposed
monkeys
had
higher
response
rates
and
the
peak
of
their
dose‐response
curve
was
0.003
mg/kg/injection
compared
to
controls
whose
peak
was
a
full
log‐unit
higher,
0.03
mg/kg/injection.
This
could
indicate
the
prenatally
cocaine‐exposed
187
monkeys
are
more
sensitive
to
the
reinforcing
effects
of
cocaine.
However,
during
maintenance
sessions,
the
dose‐response
curve
shifted
to
the
right
for
the
prenatally
cocaine‐exposed
monkeys
so
it
was
now
identical
to
the
control
monkeys’
dose‐response
curve.
Therefore,
under
an
FR
schedule
of
reinforcement,
the
initial
increased
sensitivity
is
no
longer
present.
Other
schedules
of
reinforcement,
like
choice
studies
or
progressive‐ratio
(PR)
studies,
should
be
examined
to
determine
if
the
reinforcing
strength
of
cocaine
is
the
same
between
the
two
groups.
PRENATAL
COCAINE
DOSE­RESPONSE
EFFECTS
In
the
prenatal
drug
exposure
literature,
there
is
debate
about
whether
the
cumulative
dose
over
gestation
or
the
maximum
dose
used
on
a
single
occasion
is
the
primary
determinant
of
adversive
outcome
(Frank
et
al.,
1998).
Based
on
neonatal
size
at
birth,
neonatal
behavior,
and
infant
informational
processing,
it
appears
that
in
the
human
literature
there
is
a
cocaine
dose‐effect
relationship
(Jacobson
et
al.,
1996;
Hurt
et
al.,
1997;
Chiriboga
et
al.,
1999;
Bateman
and
Chiriboga,
2000).
One
of
the
advantages
of
the
cohort
examined
in
this
dissertation
is
that
the
prenatally
cocaine
exposed
monkeys
varied
in
their
cumulative
dose
of
cocaine
they
were
exposed
to
throughout
gestation
as
well
as
varied
in
their
maximal
dose
used
on
a
single
occasion.
Therefore,
we
could
examine
whether
there
was
a
dose
effect
relationship
that
could
be
observed
in
adulthood.
In
Chapter
II,
we
188
determined
that
there
was
a
significant
positive
correlation
between
the
daily
maximal
dose
of
cocaine
each
monkey
was
exposed
to
in
utero
and
D3
receptor
function.
However,
when
cumulative
gestational
cocaine
exposure
was
used
in
the
analysis,
the
correlation
was
no
longer
significant.
All
the
other
measures
discussed
in
Chapters
III
and
IV
were
also
examined
for
an
in
utero
cocaine
dose
effect
relationship.
Although
there
was
a
trend
for
a
negative
correlation
between
sessions
to
acquire
cocaine
self‐administration
and
cumulative
gestational
cocaine
exposure
dose,
it
was
not
significant
(r2
=
0.16,
p
=
0.1;
data
not
shown).
No
other
measures
were
revealed
to
have
a
relationship
to
either
cumulative
gestational
cocaine
dose
or
maximal
dose
received
on
a
single
occasion.
This
suggests
while
there
may
a
dose
effect
relationship
present
(as
evident
by
the
D3
function
and
acquisition
of
self‐
administration
data),
it
is
challenging
to
observe
in
adulthood,
years
after
the
prenatal
cocaine
exposure.
MULTIPLE
ASPECTS
OF
IMPULSIVITY
It
has
been
said
that,
“Impulsivity
is
key
to
understanding
the
phenomenology
of
externalizing
disorders,
such
as
addiction”
(J.D.
Jentsch,
2010).
Impulsivity,
as
it
relates
to
substance
abuse,
has
been
described
as
difficulty
with
interrupting
and
inhibiting
automatic
responses.
Since
drug
dependence
is
characterized
by
risky
drug‐taking
behavior
and
repeated
failure
to
reduce
drug‐taking,
dysfunction
of
the
impulse
control
systems
may
play
a
key
role
in
addiction.
Willful
and
active
suppression
of
drug‐
189
taking
behavior
requires
being
able
to
voluntarily
modulate
impulsive
thoughts
and
action
to
inhibit
impulsive
drug‐seeking
and
drug‐taking.
Trait
impulsivity
is
rapid,
unplanned
inflexible
approach
to
novelty
or
to
rewards
and
can
be
examined
by
novel
object
reactivity.
High
novelty‐
seeking
individuals
are
considered
impulsive
(Cloninger,
1987)
and
this
temperament
has
been
linked
in
the
general
population
to
drug
addiction
and
impulse
control
disorders
(Kim
and
Grant,
2001).
Discounting
tasks
are
thought
to
measure
a
slightly
different
aspect
of
impulsivity,
impulsive
decision‐making
or
choice
rather
than
impulsive
behavior
(Jentsch,
2008).
Impulse
control
can
be
examined
by
reversal
learning
or
perseveration
tasks.
Since
impulsivity
is
a
multi‐factorial
construct,
it
stands
to
reason
that
various
tasks
to
assess
impulsivity
rely
upon
only
partially
overlapping
neural
circuitry.
Impulsive
choice
tasks
like
delay
discounting
have
been
linked
to
the
anterior
cingulate
cortex,
medial
prefrontal
cortex,
and
nucleus
accumbens
core
(Cardinal
et
al.,
2001;
2004)
while
impulse
control
of
response
adaptation
(e.g.,
reversal
learning)
depends
upon
orbitofrontal
cortex
and
its
efferent
targets
in
the
medial
striatum
(Dias
et
al.,
1996;
Schoenbaum
et
al.,
2002;
Chudasama
and
Robbins,
2003;
Fellows
and
Farah,
2003;
Boulougouris
et
al.,
2007;
Clarke
et
al.,
2008).
If
these
tasks
are
neurally
independent,
then
their
individual
relationships
to
addiction
may
vary
as
well.
One
cognitive
component
of
the
impulse
control
system
is
the
ability
to
stop,
withhold,
or
change
responses.
Reversal
learning
selectively
190
measures
the
ability
to
change
or
inhibit
a
conditioned
response.
Deficits
in
reversal
learning
has
been
shown
to
be
predictive
of
the
prognosis
of
drug‐
dependent
individuals
in
treatment,
with
those
with
the
most
deficits
on
the
task,
who
show
the
most
perseveration
of
responding,
being
linked
to
relapse
(Paulus
et
al.,
2005).
In
animal
studies,
Jentsch
and
colleagues
have
determined
that
even
short‐term
(2
weeks)
exposure
to
cocaine
can
produce
long‐lasting
impairments
in
reversal
learning
(Jentsch
et
al.,
2002;
Olausson
et
al.,
2007).
These
impairments
have
also
been
observed
in
rats
that
self‐
administer
cocaine
(Calu
et
al.,
2007)
and
human
cocaine
addicts
(Fillmore
and
Rush,
2006;
Ersche
et
al.,
2008),
indicating
that
this
is
a
robust
effect.
Additionally,
a
recent
study
revealed
that
this
deficit
in
inhibition
of
behavior
may
be
specific
to
cocaine
as
individuals
who
abuse
drugs
other
than
cocaine
did
not
show
the
same
perseverative
responding
in
a
reversal
learning
task
as
cocaine
abusers
(Ersche
et
al.,
2008).
Exposure
to
drugs
of
abuse
in
adulthood
can
also
impair
impulsive
choice.
Rats
chronically
exposed
to
cocaine
exhibit
less
ability
to
delay
gratification
than
saline‐treated
controls
(Paine
et
al.,
2003;
Simon
et
al.,
2007).
Cocaine‐exposed
rats
also
exhibit
hypersensitivity
to
changes
in
reward
delay
and
magnitude
(Roesch
et
al.,
2007).
Collectively,
the
literature
provides
evidence
that
the
direct
pharmacological
effects
of
drugs
of
abuse
can
alter
impulsive
responding
and
choice
in
laboratory
animals.
These
changes
may
mirror
similar
deficits
in
performance
in
drug‐dependent
individuals
(Jentsch,
2008)
which
indicates
191
these
laboratory
measures
may
be
useful
analogous
or
homologous
behavioral
assessments.
In
Chapter
III,
we
determined
that
prenatally
cocaine‐exposed
monkeys
were
more
impulsive
than
controls
across
a
variety
of
measures.
Although
we
did
not
observe
differences
in
novel
object
reactivity
or
locomotor
activity
in
a
novel
environment,
monkeys
exposed
to
cocaine
in
utero
displayed
more
response
perseveration
during
extinction
of
food‐
reinforced
behavior
than
controls.
This
is
similar
to
earlier
work
with
these
same
monkeys
when
they
were
much
younger.
Chelonis
et
al.
(2003)
showed
the
prenatally
cocaine‐exposed
monkeys
displayed
response
perseveration
for
two
and
half
years
when
the
rules
were
reversed
on
a
simple
visual
discrimination
task
compared
to
controls,
which
the
authors
believed
indicated
that
these
animals
have
greater
difficulty
adapting
to
important
changes
in
their
environment.
In
both
Paule
and
colleagues’
study
and
in
our
experiments,
all
the
monkeys
acquired
the
original
task
equally
well
but
the
prenatally
cocaine
exposed
monkeys
(highly
impulsive)
perseverated
much
longer
than
control
monkeys
(low
impulsive),
indicating
difficulty
inhibiting
what
had
become
an
automatic
response.
Additionally,
male
prenatally
cocaine‐exposed
monkeys
exhibited
greater
discounting
of
a
delayed
food
reward
than
controls,
indicating
impaired
impulsive
choice.
These
data
demonstrate
that
the
effects
of
cocaine
exposure
on
impulsive
responding
and
impulsive
choice
are
incredibly
long‐lasting
(14‐15
years
after
prenatal
exposure).
192
IMPULSIVITY
AND
COCAINE
SELF­ADMINISTRATION
It
has
been
well‐established
that
increased
impulsivity
can
be
a
direct
consequence
of
chronic
exposure
to
drugs
of
abuse,
especially
cocaine.
However,
it
is
also
thought
that
impulsivity
is
a
trait
with
naturally‐occurring
variation
that
can
be
a
risk‐factor
for
substance
abuse.
Impulsivity
is
at
least
in
part
under
genetic
control
with
more
than
13%
of
natural
variation
in
impulsive
behavior
attributed
to
variations
in
dopamine
system‐related
genes
(Bailey
et
al.,
2007;
Groman
et
al.,
2008)
and
this
may
be
a
crucial
quantitative
indicator
of
drug
abuse
liability.
Dalley
et
al.
(2007)
showed
that
rats
that
exhibited
greater
impulsive
action
on
a
choice
reaction‐time
task
subsequently
took
more
cocaine.
It
is
possible
that
there
is
a
causal
relationship
between
impulsivity
and
D2‐like
receptor
function.
The
rats
that
were
most
impulsive
and
most
vulnerable
to
cocaine
self‐administration
behavior
were
also
the
ones
with
lower
dopamine
D2‐like
receptor
availability
in
the
ventral
striatum
(Dalley
et
al.,
2007).
This
same
relationship
between
impulsivity
and
acquisition
of
nicotine
self‐
administration
has
been
observed
in
rodents
(Diergaarde
et
al.,
2008),
suggesting
this
relationship
may
be
true
for
all
stimulants.
Furthermore,
blockade
of
D2‐like
receptor
function
increases
perseverative
behavior
on
a
reversal
learning
task
in
monkeys
(Lee
et
al.,
2007).
Vulnerability
to
self‐administer
drugs
of
abuse
in
rodents
has
been
related
to
naturally
occurring
impulsivity.
For
example,
rats
that
exhibit
the
193
steepest
delay
discounting
effects
self‐administer
more
ethanol
and
cocaine
than
rats
characterized
as
less
impulsive
(Poulos
et
al.,
1995;
Perry
et
al.,
2005).
In
rats
self‐administering
nicotine,
impulsive
delay
discounting
performance
predicts
resistance
to
extinction
and
susceptibility
to
conditioned
cue
reinstatement
(Diergaarde
et
al.,
2008).
Furthermore,
naïve
animals
that
are
characterized
as
highly
impulsive
are
more
likely
compared
with
low
impulsive
animals
to
transition
sooner
to
inflexible
cocaine‐taking
that
is
resistant
to
punishment
(Belin
et
al.,
2008).
In
Chapter
IV,
we
determined
that
prenatally
cocaine
exposed
monkeys,
who
were
previously
characterized
as
more
impulsive
than
controls,
were
more
vulnerable
to
acquiring
cocaine
self‐administration.
Additionally,
the
most
impulsive
monkeys,
regardless
of
prenatal
condition,
acquired
cocaine
self‐administration
more
readily
than
the
less
impulsive
monkeys.
The
studies
we
used
to
measure
aspects
of
impulsivity
were
useful
in
defining
a
cocaine
abuse
“vulnerable”
phenotype.
Furthermore,
we
were
able
to
establish
that
the
biological
basis
of
this
predisposition
to
self‐
administer
cocaine
may
be
D3
receptor
function,
as
animals
that
displayed
the
largest
behavioral
response
to
a
D3
agonist
were
also
more
impulsive
and
more
susceptible
to
cocaine
functioning
as
a
reinforcer
than
animals
without
as
robust
D3
receptor
function.
Although
all
four
behavioral
assays
deemed
to
measure
impulsivity
were
used
in
the
calculation
of
the
impulsivity
score,
certain
tasks
may
have
more
predictive
validity
in
NHP
for
which
individuals
may
be
most
194
vulnerable
to
self‐administration.
The
two
conditioned
behavioral
measures,
delay
discounting
and
perseverative
responding
while
extinguishing
food‐
reinforced
behavior,
revealed
significant
differences
between
prenatally
cocaine
exposed
and
control
monkeys
by
themselves
while
the
two
unconditioned
behavioral
measures,
novel
object
reactivity
and
locomotor
activity,
only
revealed
trends
towards
a
difference
between
the
two
groups.
In
NHP,
more
challenging,
complex
tasks
like
the
conditioned
behavioral
measures
may
be
more
useful
for
parsing
out
differences
in
impulsivity
than
unconditioned
behavioral
measures,
which
have
traditionally
been
used
in
rodent
studies.
Although
no
one
impulsivity
measure
correlated
with
acquisition
of
self‐administration
measures,
in
Chapter
IV,
we
showed
that
monkeys
classified
as
highly
vulnerable
were
more
impulsive
overall
than
monkeys
classified
as
less
vulnerable.
Although
the
conditioned
behavioral
measures
might
be
better
suited
for
detecting
subtle
differences
in
impulsivity,
all
measures
used
contribute
towards
predicting
predisposition
to
self‐administration
behavior.
Therefore,
there
is
still
great
value
in
using
multiple
assays
to
investigate
and
to
create
a
clearer
overall
picture
of
impulsivity.
Impulsive
behavior
has
been
shown
to
play
a
key
role
in
our
current
concepts
of
drug
abuse.
Since
animal
models
continue
to
demonstrate
the
nature
of
these
relationships
(i.e.,
chronic
drug
exposure
causes
increases
in
impulsivity
but
also
that
impulsivity
is
a
risk
factor
for
substance
abuse),
new
pharmacological
treatments
should
be
selected
for
their
ability
to
enhance
195
impulse
control
in
these
animal
models
in
order
to
ideally
reduce
drug‐
seeking
and
drug‐taking
behavior
in
addicts.
D2­LIKE
RECEPTOR
FUNCTION
D2‐like
agonists
have
a
biphasic
effect
on
yawning,
with
low‐doses
producing
a
dose‐dependent
increase
in
yawning
and
higher
doses
inhibiting
yawning
and
inducing
hypothermia
(Collins
et
al.,
2005;
2007).
These
effects
have
been
attributed
to
the
D3
and
D2
receptors,
respectively.
Collins
and
colleagues
(2005;
2007;
2008;
2009)
have
provided
support
for
these
subtype
specific
roles
by
antagonist
interaction
studies
in
which
D3‐selective
antagonists
have
been
shown
to
produce
dose‐dependent
and
selective
rightward
shifts
of
the
ascending
limb,
whereas
D2‐preferring
antagonists
have
been
shown
to
produce
a
selective
rightward
shift
of
the
descending
limb
of
the
dose‐response
curve
for
D2‐like
agonist‐induced
yawning
at
doses
that
also
inhibit
the
induction
of
hypothermia.
These
differential
roles
of
the
D3
(induction)
and
D2
(inhibition)
receptors
in
the
mediation
of
yawning,
allows
for
the
determination
of
changes
in
these
two
receptor
subtypes
after
exposure
to
cocaine
since
increases
in
D3
receptor
density
should
result
in
leftward
shifts
of
the
ascending
limb
of
the
yawning
dose‐
response
curve
while
decreases
in
D2
receptor
density
should
result
in
rightward
shifts
of
the
descending
limb
of
the
yawning
dose‐response
curve.
Collins
et
al
(in
preparation)
found
that
rats
treated
with
15
mg/kg
cocaine
i.p.
once
per
day
for
seven
days,
a
dose
that
results
in
locomotor
196
sensitization,
displayed
a
progressive
and
persistant
leftward
and
upward
shift
of
the
ascending
limb
of
the
pramipexole‐elicited
yawning
dose‐
response
curve
beginning
as
early
as
72
hours
after
the
first
injection.
This
effect
on
the
dose‐response
curve
was
apparent
even
6
weeks
after
the
cocaine
administration
had
ceased
while
the
hypothermic
response
to
pramipexole
was
unaffected
by
cocaine
treatment.
Furthermore,
it
was
determined
that
there
were
increases
in
D3
receptor
binding
using
in
vitro
[3H]7‐OH‐DPAT
binding
assays
on
membranes
prepared
from
the
ventral
striatum
tissue
collected
at
6
weeks
post‐cocaine
treatment
suggesting
the
increased
sensitivity
in
pramipexole‐elicited
yawning
was
due
to
an
upregulation
of
D3
receptors.
This
work
supports
previous
research
that
found
increases
in
D3
receptor
binding
in
the
nucleus
accumbens
core
and
ventral
caudate‐putamen
in
rats
that
self‐administered
cocaine
(0.75
mg/kg/injection)
on
a
variable‐ratio
(VR)
5
schedule
of
reinforcement
for
2
weeks
after
32
days
(but
not
2
or
8
days)
after
their
last
self‐administration
session
(Neisewander
et
al.,
2004).
In
Chapter
II,
we
used
D1‐like
and
D2‐like
agonist‐induced
behavioral
effects
in
conjunction
with
PET
measures
of
D2‐like
receptor
availability
to
determine
if
prenatal
cocaine‐exposure
affected
the
function
of
D1‐like
or
D2‐like
receptors
in
adult
rhesus
monkeys.
Interestingly,
although
the
prenatally
cocaine
exposed
monkeys
did
not
differ
from
controls
with
respect
to
PET
measures
of
D2‐like
receptor
availability
or
D1‐like
agonist‐
induced
eye
blinking,
a
significant
increase
in
quinpirole‐elicited
yawning
197
was
observed
in
monkeys
that
were
exposed
to
cocaine
in
utero
as
compared
to
controls
(Hamilton
et
al.,
2010).
Not
only
was
this
effect
positively
correlated
with
the
maximal
daily
dose
of
cocaine
received
throughout
gestation,
but
these
increases
in
quinpirole‐elicited
yawning
were
observed
13
years
after
in
utero
exposure.
This
suggests
that
cocaine
exposure
may
result
in
long‐lasting,
if
not
permanent,
enhancement
of
the
function
and/or
sensitivity
of
D3
receptors,
which
would
support
the
finding
of
upregulation
of
D3
receptors
in
the
nucleus
accumbens
of
human
cocaine
overdose
fatalities
(Staley
and
Mash,
1996;
Segal
et
al.,
1997).
The
use
of
D2‐like
PET
ligands
(e.g.,
[11C]
raclopride,
[18F]
FCP,
and
[18F]
fallypride)
has
improved
the
ability
to
conduct
longitudinal,
within
subject
studies
of
the
relationship
between
striatal
D2‐like
receptor
availability
and
behavior
in
humans,
monkeys,
and
rats
(Volkow
et
al.,
1999;
Morgan
et
al.,
2002;
Martinez
et
al.,
2004;
Nader
et
al.,
2006;
Dalley
et
al.,
2007).
However,
it
is
difficult
to
parse
the
contributions
of
changes
in
D3
receptor
availability
and/or
changes
in
the
D2
or
D3
receptor
affinity
as
these
radioligands
do
not
discriminate
between
D2
and
D3
receptors
and
are
insensitive
to
changes
in
the
functional
state
of
D2‐like
receptors.
Therefore,
another
explanation
for
the
lack
of
differences
in
D2‐like
receptor
availability
as
examined
with
PET
is
that
if
there
were
differences
in
D3
and
D2
receptor
density
(upregulated
D3,
downregulated
D2)
in
the
prenatally
cocaine
exposed
monkeys
compared
to
controls
it
could
have
been
masked
by
basal
dopamine
binding
to
receptors
differentially.
198
Dopamine
has
a
70‐fold
greater
affinity
for
the
D3
receptor
compared
to
the
D2
receptor
(Sokoloff
et
al.,
1992).
Binding
constants
for
the
dopamine
receptor
for
competition
with
dopamine
in
cloned
human
dopamine
receptors
in
vitro
[Ki
(nM)]
are
D3
=
30,
D5
=
230,
D4
=
450,
D2
=
2000,
D1
=
2300
(Sokoloff
et
al.,
1992).
Therefore,
at
a
resting
dopamine
concentration
of
5
nM,
these
relative
affinities
would
predict
that
D3
receptors
would
be
14%
occupied
while
occupancy
of
D2
receptors
would
be
about
0.2%.
If
the
dopamine
concentration
was
increased
by
the
blockade
of
the
DAT
by
a
stimulant
drug
like
cocaine
to
250
nM,
D3
receptor
occupancy
would
be
90%
while
D2
receptors
would
be
about
10%
occupied.
These
marked
differences
in
receptor
occupancy
could
result
in
differences
in
FCP
binding.
If
there
was
an
upregulation
of
D3
receptor
density,
more
dopamine
would
be
bound
to
the
D3
receptors,
allowing
FCP
to
bind
more
at
D2
receptors
in
the
prenatally
cocaine
exposed
monkeys.
If
these
monkeys
also
had
a
decrease
in
D2
receptor
density,
it
could
still
appear
the
same
using
FCP
as
control
animals
where
more
D2
receptors
are
bound
with
dopamine
(see
Figure
3).
199
PRENATALLY
COCAINE
EXPOSED
D3
receptor
D2
receptor
Dopamine
FCP
CONTROLS
D3
receptor
D2
receptor
Dopamine
FCP
200
FIGURE
3:
Despite
potential
alterations
in
D3
and
D2
receptors
in
prenatally
cocaine
exposed
monkeys,
D2‐like
receptor
availability
as
measured
by
[18F]FCP
could
still
have
been
similar
to
controls
due
to
differences
in
dopamine’s
affinity
for
the
receptor
subtypes.
To
determine
more
definitively
whether
there
was
an
upregulation
of
D3
receptors
and/or
a
downregulation
of
D2
receptors,
completive
binding
studies
could
be
done.
Administering
a
selective
D2
receptor
antagonist
prior
to
injection
of
FCP
would
allow
researchers
to
examine
just
the
D3
receptor
availability.
Likewise,
administration
of
a
selective
D3
receptor
antagonist
that
would
compete
with
dopamine
to
bind
the
D3
receptors
prior
to
FCP
injection
would
allow
for
examination
of
just
D2
receptor
availability.
Another
important
point
is
that
even
though
there
were
no
changes
detected
in
D2‐like
receptor
availability
with
PET
(Chapter
II),
once
the
animals
have
self‐administered
cocaine
chronically,
there
could
be
differences
in
the
reduction
of
D2‐like
receptor
availability
observed
between
the
two
groups.
For
example,
when
the
system
is
stressed
by
the
chronic
cocaine
exposure
in
adulthood,
the
prenatally
cocaine
exposed
monkeys
may
show
more
dramatic
decreases
in
D2‐receptor
availability
compared
to
controls.
D3
RECEPTOR
FUNCTION
AND
SELF­ADMINISTRATION
D3
receptors
may
play
a
crucial
role
in
the
reinforcing
effects
of
stimulants.
The
earliest
indicator
was
that
D3
receptors
have
a
unique
201
anatomical
distribution
with
highest
concentrations
found
in
mesolimbic
systems
that
have
been
implicated
in
drug
abuse
(Levesque
et
al.,
1992).
D3‐
preferring
agonists
can
modulate
cocaine
self‐administration
(Caine
and
Koob,
1993;
1995;
Nader
and
Mach,
1996;
Parsons
et
al.,
1996).
Moreover,
it
has
been
shown
that
the
relative
potencies
of
D2‐like
receptor
agonists
to
alter
cocaine
self‐administration
is
highly
correlated
with
their
relative
potencies
for
increasing
mitogenesis
in
vitro
in
cell
lines
expressing
D3
but
not
D2
receptors
(Caine
et
al.,
1997).
The
D3‐preferring
agonist
7‐OH‐DPAT
functions
as
a
reinforcer
in
monkeys
with
a
cocaine
self‐administration
history
but
fails
to
support
self‐administration
in
drug‐naïve
monkeys
(Nader
and
Mach,
1996).
This
suggests
that
some
alteration
in
D3
receptor
sensitivity
and/or
density
occurs
following
cocaine
exposure.
Although
D3‐selective
antagonists
have
generally
been
found
to
be
ineffective
at
decreasing
self‐administration
when
cocaine
is
available
under
a
low
FR
(i.e.,
FR
1
or
FR
2)
schedules
of
reinforcement
(Gal
and
Gyertyan,
2003;
Xi
et
al.,
2005;
Xi
et
al.,
2006),
there
is
growing
evidence
suggesting
that
the
D3
receptor
plays
an
important
role
in
drug
abuse‐related
behaviors,
like
reactivity
of
laboratory
animals
to
drug‐paired
stimuli
and
drug‐seeking
behaviors.
D3‐preferring
agonists
like
quinpirole
have
been
shown
to
induce
responding
for
stimuli
that
had
been
previously
paired
with
cocaine
reinforcement
(Collins
and
Woods,
2009).
Additionally,
a
variety
of
D3‐
selective
antagonists
and
partial
agonists
have
also
been
shown
to
inhibit
the
capacity
of
cues
to
reinstate
responding
after
some
period
of
abstinence
from
202
stimulant
self‐administration
(Vorel
et
al.,
2002;
Gilbert
et
al.,
2005;
Gal
and
Gyertyan,
2006;
Cervo
et
al.,
2007;
Khaled
et
al.,
2009).
Furthermore,
in
Chapter
IV,
we
determined
that
monkeys
that
were
most
vulnerable
to
acquisition
of
cocaine
self‐administration
had
greater
sensitivity
to
D3
agonist‐elicited
yawning
than
monkeys
that
were
less
vulnerable
to
cocaine
self‐administration.
Therefore,
it
appears
that
increased
D3
receptor
sensitivity
and/or
density
may
be
a
biological
risk
factor
for
progressing
to
stimulant
addiction
and
that
there
is
increase
in
D3
receptor
density
that
occurs
following
cocaine
exposure
that
may
be
linked
to
the
reinforcing
effects
of
cocaine
and
the
development
of
cocaine
dependence.
IMPULSIVITY
AND
D3
RECEPTOR
FUNCTION
Recently,
it
has
been
observed
that
patients
with
Parkinson’s
Disease
being
treated
with
DA
agonists
may
develop
impulse
control
disorders,
such
as
pathological
gambling,
compulsive
shopping,
and
hypersexuality
(Pontone
et
al.,
2006;
Szarkman
et
al.,
2006;
Weintraub
et
al.,
2006;
Voon
et
al.,
2007).
A
review
of
the
Food
and
Drug
Administration
adverse
events
database
revealed
that
treatment
with
DA
agonists
was
a
major
correlate
of
pathological
gambling
and
the
most
frequently
identified
medication
was
pramipexole,
the
D3
receptor
preferring
agonist
(Szarfman
et
al.,
2006).
In
fact,
pramipexole
was
identified
in
58%
of
the
67
pathological
gambling
reports
in
the
database
(which
was
not
confined
to
Parkinson’s
Disease
patients)
(Szarfman
et
al.,
2006).
A
more
recent
review
of
all
published
cases
203
of
Parkinson’s
disease
patients
that
developed
an
impulse
control
disorder,
174
out
of
177
patients
were
being
treated
with
a
DA
agonist
(Gallagher
et
al.,
2007).
This
review
also
concluded
that
incidence
of
pathological
gambling
was
as
high
as
8%
in
Parkinson’s
Disease
patients
treated
with
DA
agonists
compared
to
less
than
1%
in
the
general
population
(Gallagher
et
al.,
2007).
Although
there
have
been
questions
regarding
a
causal
relationship
between
DA
agonists
like
pramipexole
and
pathological
gambling,
evidence
for
such
a
causative
role
is
growing.
Rigorous
clinical
evaluations
have
shown
that
patients
treated
with
levodopa
alone
did
not
develop
impulse
control
disorders
while
treatment
with
pramipexole
was
predictive
of
developing
an
impulse
control
disorder
(Pontone
et
al.,
2006;
Weintraub
et
al.,
2006).
This
indicates
that
the
development
of
impulse
control
disorders
may
not
be
simply
due
to
an
increase
in
DA
signal,
but
perhaps
related
to
D3
receptor
stimulation.
In
a
follow‐up
study
with
12
Parkinson’s
Disease
patients
that
had
developed
an
impulse
control
disorder,
reducing
the
dose
of
the
DA
agonist
and
increasing
levodopa
dose
to
achieve
the
same
benefit
in
relieving
motor
symptoms
resulted
in
resolution
of
the
impulse
control
disorder
symptoms
in
all
patients
(Mamikonyan
et
al.,
2008).
Also,
an
association
has
been
shown
between
a
variant
of
the
D3
receptor
gene
DRD3,
but
not
the
D2
receptor
gene
DRD2,
and
development
of
impulse
control
disorders
in
Parkinson’s
patients
(Lee
et
al.,
2009).
204
It
appears
that
this
increased
risk
of
impulse
control
disorders
associated
with
DA
agonists
is
not
unique
to
Parkinson’s
Disease
patients.
Reports
are
emerging
of
pathological
gambling
as
a
side
effect
in
patients
with
restless
legs
syndrome
being
treated
with
pramipexole
(Tippmann‐
Peikert
et
al.,
2007;
Driver‐Dunckley
et
al.,
2007;
Ondo
and
Lai,
2008,
Cornelius
et
al.,
2010).
Ondo
and
Lai
(2008)
found
that
almost
20%
of
patients
interviewed
indicated
increased
impulsivity
with
the
use
of
DA
agonists,
specifically
pramipexole.
Furthermore,
a
statistically
significant
correlation
for
pramipexole
dose
and
impulse
control
disorders
has
been
observed
in
restless
legs
syndrome
patients
(Ondo
and
Lai,
2008;
Cornelius
et
al.,
2010).
Taken
together,
it
appears
that
the
administration
of
DA
agonists,
in
particular
the
D3
preferring
agonist
pramipexole,
can
be
a
trigger
for
development
of
pathological
gambling
and
other
impulse
control
disorders,
suggesting
a
causal
role
for
increased
D3
receptor
stimulation
and
impulsivity.
This
conclusion
is
supported
by
the
data
in
Chapters
II
and
III
that
found
prenatally
cocaine
exposed
monkeys
were
more
impulsive
than
controls
and
that
increased
D3
receptor
function
may
be
the
neurobiological
correlate
for
that
behavioral
change.
SEX
DIFFERENCES
Other
than
DA
agonist
treatment,
one
of
the
main
risk
factors
for
the
development
of
impulse
control
disorders
in
patients
with
parkinsonian‐
related
diseases
is
male
sex
(Voon
et
al.,
2007).
This
is
interesting
to
note
205
considering
the
sex
difference
observed
in
Chapters
III.
The
increase
in
overall
impulsivity
was
observed
in
male,
but
not
female,
prenatally
cocaine‐
exposed
monkeys.
Despite
the
fact
that
differences
were
observed
in
impulsivity,
in
Chapter
IV
we
did
not
find
any
sex
differences
in
acquisition
of
cocaine
self‐administration
(Figure
4),
suggesting
that
increased
D3
receptor
function
may
be
a
larger
risk
factor
for
vulnerability
to
stimulant
self‐administration
than
increased
impulsivity,
at
least
in
females.
FIGURE
4.
Percentage
of
male
(closed
symbols)
and
female
(open
symbols)
monkeys
that
reached
criteria
to
acquire
cocaine
self‐
administration
at
various
doses
of
cocaine
available
under
an
FR
30
schedule
of
reinforcement.
206
Furthermore,
the
relationship
we
found
in
individual
animals
between
impulsivity
and
D3
receptor
function
and
total
cumulative
cocaine
intake
prior
to
reaching
acquisition
criteria
was
found
in
both
male
and
female
subjects.
However,
we
had
fairly
low
power
to
detect
differences
in
the
survival
analysis
of
acquisition
of
cocaine
self‐administration
due
to
such
a
low
acquisition
rate
across
all
groups
resulting
in
censored
data.
Therefore,
it
is
possible
that
with
a
larger
cohort,
subtle
sex
differences
in
acquisition
of
cocaine
self‐adminstration
may
be
observable.
Alternatively,
other
mechanisms
may
play
a
larger
role
in
vulnerability
to
stimulant
self‐administration
behavior
in
female
subjects
than
impulsivity
and
D3
receptor
function.
For
example,
it
has
been
shown
that
estrogen
can
alter
the
response
to
cocaine
in
rats
(Sell
et
al.,
2000).
Estrogen
can
also
modulate
DA
neuron
firing
activity
in
VTA
neurons
induced
by
a
cocaine
injection
(Zhang
et
al.,
2008),
and
regulate
mRNA
expression
for
specific
DA
and
5‐HT
receptors
(Zhou
et
al.,
2002).
Studies
in
NHP
have
shown
ovarian
steroid
can
affect
functional
properties
of
the
5‐HT
neural
system
(Bethea
et
al.,
1998;
Pecins‐Thompson
et
al.,
1998;
Pecins‐
Thompson
and
Bethea,
1999).
Since
there
is
evidence
for
a
modulatory
role
of
5‐HT
in
the
behavioral
effects
of
cocaine
(Cunningham
and
Callahan,
1994;
Satel
et
al.,
1995),
ovarian
hormones
have
the
potential
to
alter
both
5‐HT
and
DA
neurotransmission
resulting
in
modification
of
the
response
to
stimulants.
It
is
possible
that
the
modulatory
role
of
5‐HT
on
response
to
cocaine
may
be
more
critical
in
females
than
in
males
for
acquisition
of
self‐
207
administration.
It
is
also
possible
that
if
we
had
examined
cocaine
self‐
administration
in
the
luteal
phase
when
estrogen
levels
are
lower
than
in
the
follicular
phase
or
if
we
had
examined
self‐administration
during
adolescence,
we
may
have
observed
sex
differences
in
the
acquisition
of
self‐
administration.
Nevertheless,
the
findings
in
this
dissertation
that
males
exposed
to
cocaine
throughout
gestation
are
more
impulsive
compared
to
controls
concurs
with
the
human
literature.
The
behavioral
issues
noted
in
children
exposed
to
cocaine
in
utero
appear
to
be
exaggerated
in
males
,
with
the
prenatally
cocaine‐exposed
boys
often
demonstrating
increased
aggression,
hyperactivity,
and
disruptive
behavior
than
non‐exposed
boys,
whereas
girls
do
not
show
these
difference
(Bendersky
et
al.,
2006;
Bennett
et
al.,
2007;
Delaney‐Black
et
al.,
2004).
Since
these
patterns
of
behavioral
issues
are
associated
with
development
of
substance
use
disorders,
it
suggests
that
these
male
children
may
be
more
vulnerable
to
stimulant
drug
taking.
CONCLUSION
The
research
presented
in
this
dissertation
further
extends
our
understanding
of
the
neurobiological
and
neurobehavioral
underpinnings
of
individual
phenotypes
related
to
vulnerability
of
drug‐taking
behavior.
The
research
in
this
dissertation
also
provides
to
the
rationale
for
the
development
of
D3
receptor
compounds
as
pharmacological
targets
for
208
treating
impulse
control
disruptions.
Beyond
pharmacological
treatment,
behavioral
interventions
could
be
implemented
with
this
high
risk
population
of
children.
For
example,
cognitive‐behavioral
therapy
has
shown
modest
success
in
decreasing
impulsive
behavior
in
adults
with
impulse
control
disorders
(Drysdale
et
al.,
2009;
Filomensky
and
Tavares,
2009;
Okuda
et
al.,
2009)
and
could
be
adapted
for
younger
children.
The
data
in
this
dissertation
suggest
that
predisposition
to
acquire
cocaine
self‐
administration
is
associated
with
increased
impulsivity
and
increased
D3
receptor
function.
Since
it
appears
that
prenatal
cocaine
exposure
increases
the
tendency
of
an
individual
having
this
vulnerable
phenotype
in
adulthood,
prenatally
cocaine
exposed
children
may
be
at
risk
for
increased
likelihood
of
stimulant
use.
209
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MH
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by
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EL
(2006)
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novel
dopamine
D3
receptor
antagonist
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effects
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of
drug‐seeking
behavior
in
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31:1393‐1405.
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199:625‐635.
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W,
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KA,
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ML
(2002)
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regulation
of
gene
expression
in
the
brain:
a
possible
mechanism
altering
the
response
to
psychostimulants
in
female
rats.
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Res
Mol
Brain
Res
100:75‐
83.
218
SCHOLASTIC
VITAE
LINDSEY
REBECCA
HAMILTON
EDUCATION:
2001‐2004
2005‐2010
Bates
College
Lewiston,
Maine
B.S.
Neuroscience;
Magna
Cum
Laude
Thesis:
Medial
septal
lesions
enhance
cocaine‐induced
suppression
of
saccharin
intake
in
rats.
Advisor:
John
E.
Kelsey,
Ph.D.
Wake
Forest
University
School
of
Medicine
Winston‐Salem,
North
Carolina
Ph.D.
Neuroscience
Dissertation:
Neurobiological
and
neurobehavioral
phenotypes
associated
with
vulnerability
to
cocaine
self‐administration
in
adult
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
Advisor:
Michael
A.
Nader,
Ph.D.
EXPERIENCE:
RESEARCH
EXPERIENCE
June
2006
–
May
2010
Jan.
2006
–
May
2006
Aug.
2005
–
Dec.
2005
Jan.
2005
–
July
2005
Graduate
Research
Michael
A.
Nader,
Ph.D.
Wake
Forest
University
School
of
Medicine
Graduate
Research
Rotation
Anthony
Liguori,
Ph.D.
Wake
Forest
University
School
of
Medicine
Graduate
Research
Rotation
Paul
W.
Czoty,
Ph.D.
Wake
Forest
University
School
of
Medicine
Post‐Baccalaureate
Research
Assistant
Roy
A.
Wise,
Ph.D.
National
Institute
on
Drug
Abuse
219
EXPERIENCE:
(CONTINUED)
May
2003
–
Dec.
2004
SCHOLASTIC
EXPERIENCE
Undergraduate
Research
Assistant
John
E.
Kelsey,
Ph.D.
Bates
College
2008
–
2009
2007‐2008
2007
Winston‐Salem
State
University
Life
Science
Department
Lecturer
and
Laboratory
Instructor
BIO
1301:
Principles
of
Biology,
5
hours/week
Wake
Forest
University
School
of
Medicine
Graduate
School
Discussion
Facilitator
Ethics
in
Science,
1
hour/week
Wake
Forest
University
Department
of
Counseling
Guest
Lecturer
Psychiatric
Pharmacology,
3
hours
2005‐2010
2003‐2004
Winston‐Salem
Public
School
System
Brain
Awareness
Council
Presentations
Drug
Addiction,
3
hours/month
Bates
College
Department
of
Neuroscience
Laboratory
Instructor
Physiological
Psychology,
3
hours/week
INSTITUTIONAL
APPOINTMENTS
AND
SERVICE:
Women’s
Health
Center
of
Excellence
Student
Representative,
2008‐2010
Program
in
Neuroscience
Recruitment
Committee
Student
Representative,
2007‐2009
Graduate
School
Professional
Development
Co‐Director,
2006‐2007
220
PROFESSIONAL
MEMBERSHIPS:
2009
–
Present
2006
–
Present
Society
for
the
Stimulus
Properties
of
Drugs
American
Society
for
Pharmacology
and
Experimental
Therapeutics
2005
–
Present
Western
North
Carolina
Society
for
Neuroscience
Chapter
2005
–
Present
2004
–
Present
Society
for
Neuroscience
Sigma
Xi
HONORS
AND
AWARDS:
2010
2010
2010
2009
Graduate
Student
Travel
Award
American
Society
for
Pharmacology
and
Experimental
Therapeutics
Graduate
Student
Best
Abstract
Award
2nd
Place
Behavioral
Pharmacology
Division
American
Society
for
Pharmacology
and
Experimental
Therapeutics
Best
Integrative
Science
Poster
Award
Wake
Forest
University
Graduate
Student
Research
Day
2009
2009
Mary
A.
Bell
Award
for
Best
Poster
and
Presentation
Behavioral
Neuroscience
Division
Western
North
Carolina
Society
for
Neuroscience
Research
Day
Best
Seminar
Award
Program
in
Neuroscience
Tutorial
Series
Best
Poster
Award
Fourth
Annual
Women’s
Health
Research
Day
221
HONORS
AND
AWARDS:
(CONTINUED)
2007
2006
2005
–
2006
2004
–
2005
2005
Best
Graduate
Student
Poster
Award
Women’s
Health
Center
of
Excellence
Western
North
Carolina
Society
for
Neuroscience
Research
Day
Best
First‐Year
Student
Tutorial
Presentation
Program
in
Neuroscience
Tutorial
Series
Graduate
Student
Fellowship
Graduate
School
of
Arts
and
Sciences
Wake
Forest
University
Post‐Baccalaureate
Intramural
Research
Training
Award
National
Institute
on
Drug
Abuse
Phi
Beta
Kappa
GRANTS:
ACTIVE
National
Institute
on
Drug
Abuse
F31
DA024485,
6/2008
–
6/2010
“Vulnerability
to
Addiction
in
Adult
Rhesus
Monkeys
Exposed
to
Cocaine
In
Utero”
PAST
Hughes
Student‐Faculty
Research
Grant,
5/2003‐8/2003
“The
Effects
of
Lesions
of
the
N.
Accumbens
Core
or
Shell
on
Context‐Specific
Locomotor
Sensitization
to
Nicotine”
PUBLICATIONS:
Hamilton
LR,
Nader
MA.
Increased
vulnerability
to
self‐administer
cocaine
in
adult
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
To
be
submitted
May
2010
to
Science.
222
PUBLICATIONS:
(CONTINUED)
Hamilton
LR,
Czoty
PW,
Nader
MA.
Increased
impulsivity
in
male,
but
not
female,
adult
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
Submitted
April
2010
to
Psychopharmacology.
Hamilton
LR,
Czoty
PW,
Gage
HD,
Nader
MA
(2010)
Characterization
of
the
dopamine
receptor
system
in
adult
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
Psychopharmacology,
210(4):481‐488.
Elmer
GI,
Pieper
JO,
Hamilton
LR,
Wise
RA
(2010)
Qualitative
differences
between
C57/BL/6J
and
DBA/2J
mice
in
morphine
potentiation
of
brain
stimulation
reward
and
intravenous
self‐
adminstration.
Psychopharmacology,
208(2):309‐21.
ABSTRACTS:
Hamilton
LR,
Wilson
WD,
Nader
MA
(2010)
Increased
vulnerability
to
cocaine
self‐administration
in
adult
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
FASEB
J
24:765.5.
Hamilton
LR,
Czoty
PW,
Nader
MA
(2010)
Impulsivity
and
vulnerability
to
cocaine
self‐administration
in
adult
rhesus
monkeys
exposed
to
cocaine
throughout
gestation.
Wake
Forest
University
Graduate
School
Student
Research
Day,
Program
No.
12.
Hamilton
LR,
Czoty
PW,
Nader
MA
(2009)
Impulsivity
and
vulnerability
to
cocaine
self‐administration
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Program
No.
842.14,
Neuroscience
Meeting
Planner.
Hamilton
LR,
Czoty
PW,
Calhoun
TL,
Nader
MA
(2009)
Impulsivity
and
vulnerability
to
cocaine
self‐administration
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
FASEB
J
23:588.9.
Hamilton
LR,
Calhoun
TL,
Nader
MA
(2009)
Increased
impulsivity
in
male,
but
not
female,
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Fourth
Annual
Women’s
Health
Research
Day,
Program
No.
3.
Hamilton
LR,
Calhoun
TL,
Nader
MA
(2008)
Increased
impulsivity
in
male,
but
not
female,
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Western
North
Carolina
Chapter
of
the
Society
for
Neuroscience
Poster
Competition,
Program
No.
5.
223
ABSTRACTS:
(CONTINUTED)
Hamilton
LR,
Gage
HD,
Calhoun
TL,
Nader
MA
(2008)
Characterization
of
the
D1,
D2,
and
D3
receptor
systems
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Johns
Hopkins
Bloomberg
School
of
Public
Health
Second
Annual
Conference
for
the
Dissemination
of
Research
on
Addiction,
Infectious
Disease,
and
Public
Health,
Program
No.
6.
Hamilton
LR,
Gage
HD,
Calhoun
TL,
Nader
MA
(2008)
Characterization
of
the
D1,
D2,
and
D3
receptor
systems
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
FASEB
J
22:904.2.
Hamilton
LR,
Gage
HD,
Calhoun
TL,
Nader
MA
(2008)
Characterization
of
the
D1,
D2,
and
D3
receptor
systems
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Wake
Forest
University
Graduate
Student
Research
Day,
Program
No.
9.
Hamilton
LR,
Gage
HD,
Calhoun
TL,
Nader
MA
(2008)
Characterization
of
the
D1,
D2,
and
D3
receptor
systems
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Wake
Forest
University
Women’s
Health
Research
Day,
Program
No
5.
Hamilton
LR,
Gage
HD,
Calhoun
TL,
Nader
MA
(2007)
Characterization
of
the
D1,
D2,
and
D3
receptor
systems
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Western
North
Carolina
Chapter
of
the
Society
for
Neuroscience
Poster
Competition,
Program
No.
12.
Hamilton
LR,
Gage
HD,
Nader
MA
(2007)
Altered
D2
receptor
availability
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
FASEB
J
21:885.13.
Czoty
PW,
Nader
SH,
Reboussin
BA,
Calhoun
TL,
Hamilton
LR,
Nader
MA
(2006)
Long‐term
cocaine
self‐administration
under
binge
conditions
or
a
second‐order
schedule
in
monkeys:
influence
of
self‐
administration.
Program
No.
123.2,
Neuroscience
Meeting
Planner.
Elmer
GI,
Pieper
JO,
Hamilton
LR,
Wise
RA,
Becker
JB,
Arnold
AP
(2005)
Sex‐chromosome
genes
influence
amphetamine
potentiation
of
brain
stimulation
reward
independently
of
gonadal
secretions
in
mice.
Program
No.
541.5,
Neuroscience
Meeting
Planner.
224
ABSTRACTS:
(CONTINUTED)
Hamilton
LR,
Elmer
GI,
Pieper
JO,
Wise
RA,
Becker
JB,
Arnold
AP
(2005)
Sex‐chromosome
genes
influence
amphetamine
potentiation
of
brain
stimulation
reward
independently
of
gonadal
secretions
in
mice.
Western
North
Carolina
Chapter
of
the
Society
for
Neuroscience
Poster
Competition,
Program
No.
16.
SEMINARS
AND
PRESENTATIONS:
Hamilton
LR,
(2010)
Effects
of
prenatal
cocaine
exposure
on
long‐
term
neurobiological
and
neurobehavioral
phenotypes
associated
with
addiction.
United
States
Army
Medical
Research
Institute
of
Chemical
Defense,
Invited
Speaker.
Hamilton
LR
(2010)
Long‐term
neurobiological
and
neurobehavioral
phenotypes
associated
with
addiction
in
rhesus
monkeys
exposed
to
cocaine
in
utero.
Yale
University,
Department
of
Psychiatry,
Invited
Speaker.
Hamilton
LR
(2010)
Impulsivity
and
vulnerability
to
addiction
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
31st
Annual
Meeting
of
the
Society
for
the
Stimulus
Properties
of
Drugs,
Keynote
Speaker.
Nader
MA,
Czoty
PW,
Nader
SH,
Hamilton
LR,
Martelle
SE,
Icenhower
M,
Riddick
NV
(2010)
What
is
implied
by
potency
differences
in
acquisition
and
maintenance
of
cocaine
self‐administration?
53rd
Annual
Behavioral
Pharmacology
Society
Meeting.
Hamilton
LR
(2009)
Long‐term
effects
of
prenatal
cocaine
exposure
in
rhesus
monkeys.
Johns
Hopkins
University,
Department
of
Psychiatry,
Behavioral
Pharmacology
Research
Unit,
Invited
Speaker.
Hamilton
LR
(2009)
Long‐term
neurobiological
and
neurobehavioral
phenotypes
associated
with
addiction
in
rhesus
monkeys
exposed
to
cocaine
in
utero.
Wake
Forest
University
School
of
Medicine,
Physiology
and
Pharmacology
Departmental
Seminar.
Hamilton
LR
(2009)
Increased
impulsivity
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Wake
Forest
University
–
Emory
University
Behavioral
Pharmacology
Symposium.
225
SEMINARS
AND
PRESENTATIONS:
(CONTINUED)
Hamilton
LR
(2009)
Sex
differences
in
the
long‐term
effects
of
prenatal
cocaine
exposure
in
rhesus
monkeys.
Wake
Forest
University
Program
in
Neuroscience
Tutorial
Series.
Hamilton
LR
(2008)
Characterization
of
the
dopaminergic
receptor
system
in
adult
rhesus
monkeys
exposed
to
cocaine
in
utero.
Wake
Forest
University
School
of
Medicine,
Physiology
and
Pharmacology
Departmental
Seminar.
Hamilton
LR
(2008)
Characterizing
the
dopaminergic
receptor
system
in
adult
rhesus
monkeys.
Wake
Forest
University
–
Emory
University
Behavioral
Pharmacology
Symposium.
Hamilton
LR
(2008)
Characterization
of
the
dopaminergic
receptor
system
in
adult
rhesus
monkeys.
Wake
Forest
University
Program
in
Neuroscience
Tutorial
Series.
Hamilton
LR
(2007)
Prenatal
cocaine
exposure
and
vulnerability
to
addiction
in
adult
rhesus
monkey.
Wake
Forest
University
School
of
Medicine,
Physiology
and
Pharmacology
Departmental
Seminar.
Hamilton
LR
(2007)
Prenatal
cocaine
exposure
and
vulnerability
to
addiction
in
adult
rhesus
monkeys.
Wake
Forest
University
–
Emory
University
Behavioral
Pharmacology
Symposium.
Hamilton
LR
(2006)
Effects
of
prenatal
cocaine
exposure
in
rhesus
monkeys.
Wake
Forest
University
–
Emory
University
Behavioral
Pharmacology
Symposium.
Hamilton
LR
(2006)
Comparison
of
marijuana
and
tobacco
withdrawal
during
a
two
week
abstinence
period.
Wake
Forest
University
Program
in
Neuroscience
Tutorial
Series.
226