1. health and fitness
2. addiction

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134
English summary
Molecular mechanisms controlling relapse to drug seeking in rodent models of addiction
Drug addiction is a psychiatric disorder that is associated with the loss of control over the
intake of drugs of abuse. This disorder is a major source of personal suffering and societal
problems. Currently, a limited number of addiction therapies are available, but these only have
minor preventive effects on relapse to the use of drugs of abuse.
During the last decades, brain imaging studies in humans have provided insight into
the brain circuitry that is involved in the development of addiction and drug craving. In parallel, animal models have been developed to study the neurobiology of addiction in more detail
and to test potential therapies. Repeated exposure to drugs induces adaptations in the brain
that persist even after extended abstinence. These neuroadaptations are thought to underlie the
chronically relapsing nature of drug addiction. It follows that a better understanding of the molecular mechanisms controlling relapse might contribute to the development of more efficient
addiction therapies. The research described in this thesis makes use of different animal models
of addiction to increase our knowledge of these mechanisms.
Chapter 2 describes the role of the extracellular matrix (ECM) in relapse to heroin
seeking in rats. After heroin self-administration and a subsequent period of extinction or abstinence, the synaptic levels of the matrix proteins brevican and tenascin-R were reduced in the
medial prefrontal cortex (mPFC), a brain area executing higher cognitive functions, of which
the involvement in relapse has been demonstrated in humans and animals. Also in the nucleus
accumbens, a brain area with an important role in reward and motivated behavior, these protein levels were reduced after extinction. Subsequently, relapse was induced by presenting the
audiovisual stimuli that were paired with injections of heroin during the self-administration
phase (“cue-induced relapse”). During relapse, ECM protein levels were partially normalized.
Furthermore, heroin seeking could be attenuated by normalizing these protein levels before the
relapse test. This indicates that reduced ECM levels might underlie a higher vulnerability for
addictive behavior.
The role of the ECM component brevican is further explored in chapter 3. To do this,
the formation of an appetitive cocaine memory was investigated in a mouse that expresses reduced levels of brevican (the Bcan+/- mouse) using the conditioned place preference paradigm.
Bcan+/- mice showed a stronger preference for the compartment that was paired with injections
of cocaine than wild-type mice. Increasing the expression level of brevican in the dorsal hippocampus, by local infusion of a viral vector with the Bcan gene, reduced the conditioned cocaine
memory. The dorsal hippocampus is a brain area that is important for contextual memo­ry.
These findings indicate that reduced brevican levels in the dorsal hippocampus underlie a
higher sensitivity for the rewarding effects of cocaine.
These studies show an important role of the ECM, and specifically brevican, in regu­
lating addictive behavior. This is consistent with available literature that shows that drugs affect
the expression or activity of ECM components, as well as the proteases that mediate their de­
135
English summary
gra­dation. Lower levels of ECM might result in increased plasticity in the brain circuitry that
is involved in addiction, and by this contribute to the formation of drug-induced neuroadaptations and the persistent vulnerability to relapse. Compounds that can modulate ECM dynamics
might therefore be employed to prevent relapse in the future.
Whereas our knowledge of the neurobiology of relapse to cocaine and heroin seeking
is increasing, little is currently known about relapse to nicotine, the neuro-active component
in tobacco. To gain insight into the acute changes that take place in the mPFC during relapse
to nicotine seeking in rats, the relapse-associated regulation of proteins that are known to have
an important role in synaptic plasticity was explored in chapter 4. Cue-induced relapse, after
nico­tine self-administration and extinction, was associated with an increase in the levels of the
α1 and γ2 subunits of the GABAA receptor, but not of subunits of glutamate receptors. Blocking
membrane insertion of GABAA receptors in the dorsal, but not the ventral, mPFC, resulted
in augmented responding during relapse. In contrast, nicotine seeking was attenuated after
infusion of the GABAA receptor agonist muscimol in the dorsal or ventral mPFC. This study
shows that cue-induced relapse to nicotine seeking is paralleled by acute GABAergic plasticity
in the mPFC. From the observation that relapse in rats can be modulated by intervening at the
level of GABAA receptors, it can be concluded that these receptors are potential targets for the
development of new, more effective therapies to support smoking cessation.
Chapter 5 describes a proteomics study that explores nicotine relapse-associated acute
protein regulation in synaptic membranes of the mPFC and the insular cortex. The insula is
a brain area that is involved in the monitoring of interoceptive states and is activated during
nicotine cravings in humans. Whereas relapse was not paralleled by molecular changes in the
insula, respectively 3 and 51 proteins were regulated during relapse in the mPFC of rats that
underwent a period of extinction or abstinence after nicotine self-administration, respectively. A reduced level of the protein Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), a transmembrane protein involved in intercellular communication, was validated in an independent group of animals that relapsed after extinction training.
These experiments show that the mPFC is subject to acute plasticity during relapse to nicotine
seeking, and that SHPS-1 is an interesting candidate for future investigations of the molecular
mechanisms that regulate relapse to nicotine seeking.
From the literature and the research described in this thesis it follows that relapse to
different drugs of abuse, such as nicotine, heroin and cocaine, is partially regulated by overlapping neural substrates. For example, the activity of and plasticity in the glutamatergic projections from the mPFC to the nucleus accumbens have a central role in regulating relapse to these
drugs. However, it can also be concluded from this thesis that relapse is regulated by molecular
mechanisms that are specific for different drugs of abuse. This indicates that, with the know­
ledge of the molecular mechanisms that regulate relapse to drug seeking, it should be possible
to develop general, as well as drug-specific, addiction therapies.
136
Nederlandse samenvatting
Moleculaire mechanismen die terugval naar drug-zoekgedrag reguleren in knaagdiermodellen van verslaving
Drugsverslaving is een psychiatrische stoornis die gepaard gaat met het verlies van controle
over het gebruik van verslavende middelen. Deze stoornis is een grote bron van persoonlijk
leed en maatschappelijke problemen. Op dit moment is een beperkt aantal behandelingen voor
verslaving beschikbaar, maar deze hebben slechts een gering effect op terugvallen in het ge­
bruik van het verslavende middel.
In de afgelopen decennia hebben hersenscans inzicht verschaft in het hersencircuit
dat betrokken is bij het ontwikkelen van een verslaving en het verlangen naar drugs. Parallel aan deze humane studies zijn diermodellen ontwikkeld om de neurobiologie van versla­
ving in meer detail te bestuderen en om mogelijke behandelmethoden te testen. Herhaalde
blootstelling aan drugs leidt tot adaptaties in de hersenen die, zelfs na een lange periode van
onthouding, blijven voortbestaan. Deze neuroadaptaties worden verondersteld ten grondslag
te liggen aan het blijvende risico op terugval dat karakteristiek is voor verslaving. Hieruit volgt
dat een beter begrip van de moleculaire mechanismen die terugval reguleren op termijn kan
bijdragen aan het ontwikkelen van efficiëntere behandelmethoden voor drugsverslaving. Het
onderzoek beschreven in dit proefschrift maakt gebruik van diermodellen van verslaving om
onze kennis van deze mechanismen te vergroten.
Hoofdstuk 2 beschrijft de rol van de extracellulaire matrix (ECM) bij terugval naar
heroïne-zoekgedrag in ratten. Na zelftoediening van heroïne en een daaropvolgende periode
van extinctie of abstinentie waren de synaptische niveaus van de matrixeiwitten brevican en
tenascin-R verlaagd in de mediale prefrontale cortex (mPFC). Dit is een hersengebied met
hogere cognitieve functies waarvan de betrokkenheid bij terugval in zowel mensen als dieren
is aangetoond. Ook in de nucleus accumbens, een hersengebied met een belangrijke rol in
belo­ning en gedragsmotivatie, waren deze eiwitniveaus verlaagd na extinctie. Vervolgens werd
terug­val geïnduceerd door audiovisuele stimuli te presenteren die tijdens de zelftoedieningsfase
werden gekoppeld aan injecties met heroïne (“cue-geïnduceerde terugval”). Tijdens terugval
vond een gedeeltelijke normalisatie plaats van de niveaus van de ECM eiwitten. Door deze
eiwitten vóór terugval te normaliseren kon het heroïne-zoekgedrag worden verlaagd. Hieruit
volgt dat verlaagde niveaus van de ECM mogelijk gepaard gaan met een hogere kwetsbaarheid
voor verslavingsgedrag.
In hoofdstuk 3 is de rol van de ECM component brevican verder onderzocht. Hier­
voor werd het vormen van een cocaïnegeheugen in een muismodel met een verlaagd expressie­
niveau van brevican (de Bcan+/- muis) onderzocht met behulp van het conditioned place
preference para­digma. Bcan+/- muizen lieten een sterkere preferentie zien voor een omgeving
die gekoppeld was aan injecties met cocaïne dan wild-type muizen. Het verhogen van de expressie van brevican in de dorsale hippocampus, door middel van het lokaal injecteren van
een virale vector met het Bcan gen, resulteerde in een vermindering van dit geconditioneerde
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Nederlandse samenvatting
geheugen aan cocaïne. De dorsale hippocampus is een hersengebied dat belangrijk is voor het
contextuele geheugen. Deze bevindingen wijzen op een verhoogde gevoeligheid voor het belonende effect van cocaïne als gevolg van verlaagde expressieniveaus van brevican in de dorsale
hippocampus.
Deze studies onderschrijven de belangrijke rol van de ECM, en in het bijzonder bre­
vican, in het reguleren van verslavingsgedrag. Ook is dit consistent met eerdere publicaties die
laten zien dat drugs een effect hebben op de expressie of activiteit van zowel componenten van
de ECM als van de proteases die de ECM afbreken. Mogelijk leiden lagere niveaus van de ECM
tot een verhoogde plasticiteit in het hersencircuit dat betrokken is bij verslaving en dragen ze zo
bij aan de vorming van drug-geïnduceerde neuroadaptaties en de langdurige gevoeligheid voor
terugval. Mogelijk kunnen stoffen die de dynamiek van de ECM beïnvloeden in de toekomst
gebruikt worden om terugval te voorkomen.
Terwijl onze kennis van de neurobiologie van terugval naar cocaïne- en heroïne-zoekgedrag toeneemt, is er nog weinig bekend over terugval naar nicotine, de neuro-actieve component in tabak. Om inzicht te krijgen in de acute veranderingen in de mPFC tijdens terugval
naar nicotine-zoekgedrag in ratten, is in hoofdstuk 4 gekeken naar de regulatie van eiwitten
die een belangrijke rol spelen in synaptische plasticiteit. Cue-geïnduceerde terugval, na zelftoediening van nicotine en extinctie, ging gepaard met een verhoging van het niveau van α1- en
γ2-subunits van de GABAA receptor, maar niet van glutamaatreceptoren. Het blokkeren van
membraaninsertie van GABAA receptoren in de dorsale mPFC, maar niet in de ventrale mPFC,
leidde tot een hoger aantal responsen tijdens terugval. Daarentegen lieten ratten minder nicotine-zoekgedrag zien na infusie van de GABAA receptor agonist muscimol in de dorsale of
ventrale mPFC. Deze studie laat zien dat cue-geïnduceerde terugval naar nicotine-zoekgedrag
gepaard gaat met acute GABAerge plasticiteit in de mPFC. Uit de observatie dat terugval in
ratten beïnvloed kan worden door in te grijpen op het niveau van GABAA receptoren volgt dat
deze receptoren mogelijke targets zijn voor de ontwikkeling van nieuwe, effectievere behandelingen om het stoppen met roken te ondersteunen.
Hoofdstuk 5 beschrijft een proteomics studie die terugval-geassocieerde acute eiwitregulatie in synaptische membranen van de mPFC en de insula in kaart brengt. De insula is een
hersengebied dat betrokken is bij het verwerken van zintuiglijke waarnemingen en wordt geactiveerd tijdens hunkering naar nicotine in mensen. Terugval ging niet gepaard met molecu­laire
veranderingen in de insula. Daarentegen werden in de mPFC van ratten die na nicotine zelftoediening een periode van extinctie en abstinentie doorliepen respectievelijk 3 en 51 eiwitten
geïdentificeerd die gereguleerd werden tijdens terugval. De verlaagde niveaus van het eiwit Src
homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), een transmembraaneiwit dat betrokken is bij intercellulaire communicatie, werden opnieuw gevonden
in een onafhankelijke groep ratten waarin terugval werd geïnduceerd na extinctie. Deze experi­
menten laten zien dat, parallel aan terugval naar nicotine-zoekgedrag, acute plasticiteit plaatsvindt in de mPFC en dat SHPS-1 een interessante kandidaat is voor vervolgonderzoek naar de
moleculaire mechanismen die terugval naar nicotine-zoekgedrag reguleren.
Uit de literatuur en het onderzoek beschreven in dit proefschrift volgt dat terugval
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Nederlandse samenvatting
naar verschillende drugs, zoals nicotine, heroïne en cocaïne, deels gereguleerd wordt door
overlappende neurale substraten. Zo spelen de activatie van en plasticiteit in de glutamaterge
projecties van de mPFC naar de nucleus accumbens een centrale rol in het reguleren van terug­
val naar deze drugs. Echter, uit het hier beschreven onderzoek volgt dat terugval ook gere­
guleerd wordt door moleculaire mechanismen die specifiek zijn voor de drug die aan de basis
staat van de verslaving. Hieruit volgt dat met de kennis van de moleculaire mechanismen die
terugval naar drug-zoekgedrag reguleren, het mogelijk zou moeten zijn zowel algemene als
drug-specifieke behandelingen te ontwikkelen.
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Acknowledgements
The little book about molecular mechanisms of addictive behavior is finally here. It proved to
be highly rewarding to be dependent on so many people to get to this point and I would like to
thank everyone that was involved in one way or the other.
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Acknowledgements
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Curriculum vitae
Bart Lubbers was born on the 25th of May, 1982. He grew up in Lonneker, where he atten­
ded the St. Liduinaschool. After graduating from the Twentsch Carmel Lyceum in Oldenzaal
in 2000, he studied Molecular Sciences at Wageningen Universiteit en Researchcentrum. He
was an active member of several committees and the board of the study organization, MSV
Alchimica. During internships in Wageningen and at the University of California in Davis, he
worked on the biochemical characterization of ligand-activated transcription factors. In 2006,
he received his master’s degree cum laude and enrolled in the research master Behavioural
and Cognitive Neuroscience at Rijksuniversiteit Groningen. After completing the curriculum,
including internships in Groningen (cortical plasticity) and Amsterdam (neuronal regeneration), he graduated cum laude. From 2008 to 2013 he performed his doctoral research on the
molecular mechanisms of relapse to drug seeking at the department of Molecular and Cellular
Neurobiology of the Vrije Universiteit in Amsterdam, under supervision of prof.dr. Guus Smit,
prof.dr. Sabine Spijker, prof.dr. Taco de Vries and dr. Michel van den Oever. In the second half
of 2013, Bart participated in the Nationale DenkTank 2013, a multidisciplinary group of young
academics that aimed to contribute to a sustainable healthcare system with novel initiatives. In
2014, he was one of the founders and board members of one of these initiatives, de Advieswinkel, which aims to normalize mental problems and increase the accessibility of mental healthcare. He currently works as business developer and project manager at Sylics.
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