L'addiction est un comportement compulsif de recherche et de prise de drogues alternant des phases d'abstinence et de rechute malgré les conséquences négatives sur la vie de l'individu. Les êtres humains ne sont pas égaux devant l'addiction et les mécanismes moléculaires sous jacents sont encore mal compris. De nombreuses structures cérébrales, telles que l'aire tegmentale ventrale (VTA), le cortex préfrontal ou l'amygdale convergent sur le noyaux accumbens (NAc) pour réguler les circuits de la " récompense ". Les neurones GABAergiques épineux de taille moyenne (MSN) sont à la fois la voie d'entrée et de sortie majeure du NAc. Les MSNs sont régulés de façon dynamique par les fibres dopaminergiques provenant de la VTA ainsi que par les interneurones cholinergiques locaux (TANs). La destruction sélective des TANs entraine une importante modification des propriétés renforçantes des psychostimulants tel que la cocaïne. En 2002 nous avons découvert que, de façon surprenante, ces neurones expriment à la fois le transporteur vésiculaire de l'acétylcholine (VAChT) et le transporteur vésiculaire du glutamate de type 3 (VGLUT3). Plus récemment nous avons établi que VGLUT3 augmentait le stockage vésiculaire ainsi que la libération d'acétylcholine (ACh) par un mécanisme que nous avons appelé " synergie vésiculaire ". De plus, il a été observé que VGLUT3 confère aux TANs la capacité d'utiliser le glutamate aussi bien qu'avec l'ACh pour communiquer. De façon surprenante, des souris ayant perdu la capacité de libérer l'ACh dans le NAc ne présente que très peu d'altération de leurs réponses comportementales à la cocaïne. Ce résultat suggère que l'ACh n'est pas indispensable à la régulation des comportements de « récompense ». 1.2 Afin de déterminer le rôle de la signalisation VGLUT3-dépendante par les TANs nous avons utilisé une souris n’exprimant plus VGLUT3. Au cours de cette thèse j’ai pu établir que l’absence de VGLUT3 exacerbe les effets comportementaux induit par la cocaïne. Il semble donc que les TANs utilisent l’ACh ou le glutamate pour réguler différentiellement la libération de DA. Nous avons des résultats préliminaires suggérant que le glutamate libéré par les TANs va activer des mGluR qui exercent un contrôle inhibiteur sur la libération de DA. De plus j’ai observé que l’augmentation de libération de DA chez les souris VGLUT3-KO entraine une activation des cascade de signalisation DR1-dépendantes. De plus les MSNs du NAc des souris VGLUT3-KO présentent des augmentations morphologiques et synaptiques de l’activité glutamatergique du NAc. Finalement une augmentation de la fréquence des mutations du gène codant pour VGLUT3 a été trouvée dans une cohorte de sujets souffrants de formes sévères d’addictions. L’ensemble de ces résultats suggère que la régulation concomitante de la signalisation DAergique et glutamatergique dans le NAc agit comme un filtre protecteur contre les effets renforçant de la cocaïne. / Drug addiction is a compulsive pattern of drug-taking/drug-seeking behavior with alternate phases of abstinence and relapse despite adverse consequences. Human beings are not equally susceptible to addictions and molecular mechanisms underlying addiction are still poorly understood. Numerous brain structures such as the ventral tegmental area (VTA), the prefrontal cortex, the amygdala or the hippocampus converge onto the nucleus accumbens (NAc) to regulate reward. GABAergic medium spiny neurons (MSN) are the major input target as well as output pathway of the NAc. MSNs are dynamically regulated by dopaminergic fibers originating from the VTA and by local tonically active cholinergic interneurons (TANs). The selective destruction of TANs modulates rewarding properties of psychostimulant such as cocaine. Twelve years ago we made the surprising discovery that these neurons express both the vesicular acetylcholine transporter (VAChT) and the vesicular glutamate transporter type 3 (VGLUT3). We recently established that VGLUT3 increases the acetylcholine (ACh) vesicular accumulation (and release) by a mechanism named vesicular synergy. Furthermore, the presence of VGLUT3 confers to TANs the ability to release glutamate in addition to ACh. Unexpectedly, mice that have lost the ability to secrete ACh in the NAc show minimal alteration of their behavioral response to cocaine. This result suggests that ACh is not sufficient to modulate reward.To investigate the role of VGLUT3-mediated signaling by TANs we used a mouse line that no longer expressed VGLUT3. During this PhD I established that silencing VGLUT3 in mice dramatically exacerbated cocaine-induced behaviors. Furthermore, we found that VAChT-KO and VGLUT3-KO mice showed a decreased and increased DA release (respectively) in the NAc. Therefore, TANs use ACh and glutamate to differentially regulate DA release. We have preliminary data suggesting the glutamate released by TANs activate mGluR that negatively control DA release. I further observed that in VGLUT3-KO mice the increased DA release enhanced DR1-signaling cascades. In addition, MSNs from the NAc of VGLUT3-KO mice had increased morphologic and synaptic glutamatergic activity in the NAc. Finally, we report non-synonymous mutations in the gene encoding VGLUT3 in patients with severe addictions. Our results suggested that the concomitant regulation of the dopaminergic and glutamatergic tone by VGLUT3 in the NAc acted as a protective filter against reinforcing properties of cocaine.

A área tegmental ventral (VTA) contém neurônios dopaminérgicos do grupamento A10 e envia projeções muito densas para o estriado ventral. Esta circuitaria está crucialmente envolvida em mecanismos de recompensa. Recentemente, a organização destas projeções foi reexaminada por Ikemoto S. (Brain Res. Rev., 56:27-78, 2007), em um estudo de rastreamento retrógrado minucioso, sendo proposto a subdivisão destas projeções em um sistema dopaminérgico mesoestriatal ventromedial que inerva a concha medial do accumbens e o tubérculo olfatório medial, e um sistema dopaminérgico mesoestriatal ventrolateral que inerva o cerne e a concha lateral do accumbens e o tubéculo olfatório lateral. Afim de complementar o conhecimento destas projeções, no presente estudo elas foram examinadas com a técnica anterógrada da leucoaglutinina do Phaseolus vulgaris. Nossos resultados indicam que há um extenso embricamento dos campos terminais estriatais inervados por diferentes setores/núcleos da VTA e reforçam a noção de que as eferências da VTA podem ser subdivididas em um sistema mesoestriatal ventromedial e um sistema mesoestriatal ventrolateral. Eles revelam ainda que as projeções da VTA para o estriado ventral têm uma organização topográfica médio-lateral mais complexa do que previamente reconhecido, a faixa médio-lateral do estriado ventral inervada depende de uma combinação da região médio-lateral e dorsoventral da VTA. Assim, as regiões mais ventrais e mediais da VTA (correspondendo ao núcleo interfascicular) inervam os distritos mais mediais do estriado ventral (a concha dorsomedial do accumbens e a extremidade medial do tubérculo olfatório), e as regiões mais dorsais e laterais da VTA (correspondendo à região dorsolateral do núcleo parabraquial pigmentoso) se projetam para os distritos mais laterais do estriado ventral (o cerne lateral e a concha lateral do accumbens, o caudado-putâmen ventral e o tubérculo olfatório lateral). Por outro lado, as projeções da VTA para o estriado ventral não possuem uma organização topográfica rostrocaudal. Outro fato a ser destacado é que a organização das projeções mesoestriatais da VTA lembra o padrão das projeções córticoestriatais, sendo observado no estriado, além de um campo terminal principal, pequenos focos isolados de marcação. / The ventral tegmental area (VTA) contains dopaminergic neurons of the A10 group and sends dense projections to the ventral striatum. This circuitry is critically involved in reward mechanisms. Recently, the organization of these projections was reexamined by Ikemoto S. (Brain Res. Rev., 56:27-78, 2007) in a detailed retrograde tracing study, being proposed that these projections can be subdivided into two main systems, a ventromedial mesostriatal dopaminergic system that innervates the medial shell of the accumbens and medial olfactory tubercle, and a ventrolateral mesostriatal dopaminergic system that targets the core and lateral shell of the accumbens and lateral olfactory tubercle. In order to complement these data, in the present study the VTA mesostriatal projections were examined with a sensitive anterograde tracing technique using the Phaseolus vulgaris leucoaglutinin. Our results indicate that there is an extensive overlap of terminal fields innervated by different sectors / nuclei of the VTA and reinforce the notion that VTA efferents can be subdivided into a ventromedial and a ventrolateral mesostriatal system. They also show that the VTA projections to the ventral striatum have a mediolateral topographical organization more complex than previously acknowledged. In fact, projections along the mediolateral dimension of the ventral striatum depends on a combination of the mediolateral and dorsoventral axis of the VTA. In other words, the most ventral and medial parts of the VTA (corresponding to the interfascicular nucleus) innervates the most medial districts of the ventral striatum (corresponding to the dorsomedial shell of the accumbens and medial tip of the olfactory tubercle), and the most dorsal and lateral parts of the VTA (corresponding to the dorsolateral region of the parabrachial pigmented nucleus) project to the most lateral districts of the ventral striatum (lateral core and lateral shell of the accumbens, ventral caudate-putamen and lateral olfactory tubercle). Moreover, VTA projections to the ventral striatum do not seem to have a rostrocaudal topographical organization. It is also of note that the organization of the VTA mesostriatal projections shares features with cortico-striatal projections, in the sense that both fiber systems have a main terminal field and also give rise to small, scattered isolated foci of terminal labeling.

La malnutrition et la consommation de cannabis font partie des grands problèmes de santé publique.L'objectif de cette thèse était d’étudier les conséquences de ces facteurs externes sur les voies mésocorticolimbiques.Le système endocannabinoïde est un complexe multimoléculaire incluant les endocannabinoïdes (eCB), molécules lipidiques synthétisées à partir des oméga-3, les enzymes de synthèse et de dégradation des eCB, et les récepteurs aux cannabinoïdes de type 1 (CB1R), principale cible du cannabis. Nos travaux montrent qu’une alimentation déficiente en oméga-3, tout comme une exposition prénatale aux cannabinoïdes, altère la signalisation endocannabinoïde dans les régions étudiées. Nous avons découvert des altérations sévères du répertoire comportemental émotionnel et cognitif chez les souris déficientes en oméga-3 corrélées à des déficits spécifiques de la plasticité synaptique dépendante du complexe de signalisation mGlu5/eCB dans le PFC et le NAc. Nous avons mis en évidence une divergence sexuelle des effets à long-terme induits par une exposition prénatale aux cannabinoïdes chez la progéniture à l’âge adulte. Nous avons observé une diminution de l’interaction sociale chez les mâles mais pas chez les femelles exposés in-utero aux cannabinoïdes. Ce déficit comportemental était associé à une hyperexcitabilité des neurones pyramidaux et à l’absence spécifique de la plasticité synaptique endocannabinoïde dans le PFC des mâles. Enfin, dans nos deux modèles d’étude, la potentialisation pharmacologique du complexe macromoléculaire de signalisation mGlu5/eCB normalise les déficits synaptiques et comportementaux, ouvrant la voie sur de nouvelles cibles thérapeutiques. / Malnutrition and the use of cannabis are amongst the public’s most signficant problems. In the past decades, drastic dietary changes are accompanied by low consumption of essential omega-3 polyunsaturated fatty acids (PUFAs). Cannabis is the most frequently used illicit drug by pregnant women and young women of reproductive age. This thesis aimed to study the consequences of these environmental factors on synaptic and behavioral functions of the mesocorticolimbic system, particularly the nucleus accumbens (NAc) and prefrontal cortex (PFC). The endocannabinoid system is a multimolecular complex including endocannabinoids (eCB), lipidic molecules synthesized from PUFAs, eCB synthesizing and degradating enzymes, and cannabinoid receptor type 1 (CB1R), the main target of cannabis. Our work shows that an omega-3 deficiency, as well as PCE, alters endocannabinoid-signaling in the areas of interest.We found severe alterations in the emotional and cognitive behavioral repertoire of omega-3 deficient mice that correlated with specific alterations in synaptic plasticity mediated by mGlu5/eCB signaling complex in PFC and NAc.We showed a sexual divergence in the long-term effects of PCE in adult offsprings. We observed a decrease in social interaction in males but not in females prenatally exposed cannabinoids. This behavioral deficit was associated with hyperexcitability of the pyramidal neurons and a specific lack of endocannabinoid synaptic plasticity in the male PFC.Finally, in our two study models, pharmacological enchancement of the mGlu5/eCB macromolecular signaling complex normalized synaptic and behavioral deficits, illuminating routes to new therapeutic targets.

A área tegmental ventral (VTA) contém neurônios dopaminérgicos do grupamento A10 e envia projeções muito densas para o estriado ventral. Esta circuitaria está crucialmente envolvida em mecanismos de recompensa. Recentemente, a organização destas projeções foi reexaminada por Ikemoto S. (Brain Res. Rev., 56:27-78, 2007), em um estudo de rastreamento retrógrado minucioso, sendo proposto a subdivisão destas projeções em um sistema dopaminérgico mesoestriatal ventromedial que inerva a concha medial do accumbens e o tubérculo olfatório medial, e um sistema dopaminérgico mesoestriatal ventrolateral que inerva o cerne e a concha lateral do accumbens e o tubéculo olfatório lateral. Afim de complementar o conhecimento destas projeções, no presente estudo elas foram examinadas com a técnica anterógrada da leucoaglutinina do Phaseolus vulgaris. Nossos resultados indicam que há um extenso embricamento dos campos terminais estriatais inervados por diferentes setores/núcleos da VTA e reforçam a noção de que as eferências da VTA podem ser subdivididas em um sistema mesoestriatal ventromedial e um sistema mesoestriatal ventrolateral. Eles revelam ainda que as projeções da VTA para o estriado ventral têm uma organização topográfica médio-lateral mais complexa do que previamente reconhecido, a faixa médio-lateral do estriado ventral inervada depende de uma combinação da região médio-lateral e dorsoventral da VTA. Assim, as regiões mais ventrais e mediais da VTA (correspondendo ao núcleo interfascicular) inervam os distritos mais mediais do estriado ventral (a concha dorsomedial do accumbens e a extremidade medial do tubérculo olfatório), e as regiões mais dorsais e laterais da VTA (correspondendo à região dorsolateral do núcleo parabraquial pigmentoso) se projetam para os distritos mais laterais do estriado ventral (o cerne lateral e a concha lateral do accumbens, o caudado-putâmen ventral e o tubérculo olfatório lateral). Por outro lado, as projeções da VTA para o estriado ventral não possuem uma organização topográfica rostrocaudal. Outro fato a ser destacado é que a organização das projeções mesoestriatais da VTA lembra o padrão das projeções córticoestriatais, sendo observado no estriado, além de um campo terminal principal, pequenos focos isolados de marcação. / The ventral tegmental area (VTA) contains dopaminergic neurons of the A10 group and sends dense projections to the ventral striatum. This circuitry is critically involved in reward mechanisms. Recently, the organization of these projections was reexamined by Ikemoto S. (Brain Res. Rev., 56:27-78, 2007) in a detailed retrograde tracing study, being proposed that these projections can be subdivided into two main systems, a ventromedial mesostriatal dopaminergic system that innervates the medial shell of the accumbens and medial olfactory tubercle, and a ventrolateral mesostriatal dopaminergic system that targets the core and lateral shell of the accumbens and lateral olfactory tubercle. In order to complement these data, in the present study the VTA mesostriatal projections were examined with a sensitive anterograde tracing technique using the Phaseolus vulgaris leucoaglutinin. Our results indicate that there is an extensive overlap of terminal fields innervated by different sectors / nuclei of the VTA and reinforce the notion that VTA efferents can be subdivided into a ventromedial and a ventrolateral mesostriatal system. They also show that the VTA projections to the ventral striatum have a mediolateral topographical organization more complex than previously acknowledged. In fact, projections along the mediolateral dimension of the ventral striatum depends on a combination of the mediolateral and dorsoventral axis of the VTA. In other words, the most ventral and medial parts of the VTA (corresponding to the interfascicular nucleus) innervates the most medial districts of the ventral striatum (corresponding to the dorsomedial shell of the accumbens and medial tip of the olfactory tubercle), and the most dorsal and lateral parts of the VTA (corresponding to the dorsolateral region of the parabrachial pigmented nucleus) project to the most lateral districts of the ventral striatum (lateral core and lateral shell of the accumbens, ventral caudate-putamen and lateral olfactory tubercle). Moreover, VTA projections to the ventral striatum do not seem to have a rostrocaudal topographical organization. It is also of note that the organization of the VTA mesostriatal projections shares features with cortico-striatal projections, in the sense that both fiber systems have a main terminal field and also give rise to small, scattered isolated foci of terminal labeling.

Pour comprendre comment le cerveau inhibe l'appétit en dépit d'un besoin énergétique, nous avons étudié les mécanismes neuronaux qui sous-tendent l'effet hypophagique induit par la 3,4-N-méthylén édioxyméthamphétamine (MDMA : « ecstasie ») et le stress (immobilisation forcée) car ces facteurs réduisent la faim d'un animal, même s'il est affamé. Nous montrons que la stimulation intracérébrale des récepteurs 5-HT4 de la sérotonine (R5-HT4), ou leur plus forte expression (ectopique, physiologique) dans une aire de la récompense (noyau accumbens : NAc), réduit la faim en augmentant l'action anorexigène d'un peptide de l'addiction : CART. A l'encontre de l'équilibre énergétique, l'effet anorexigène induit par la stimulation des R5-HT4 dans le NAc s'accompagne d'une hyperactivité motrice, souvent décrite chez l'humain souffrant d'anorexie mentale. En supposant qu'un effet récompensant prévaut sur le danger d'un déséquilibre énergétique, nous montrons, qu'effectivement, l'injection d'un antagoniste des R5-HT4 dans le NAc réduit les effets anorexigène, hyperlocomoteur et récompensant de la MDMA. S'il est alors récompensant de se priver d'aliments, une souris surexprimant les R5-HT4 dans le NAc, devrait, après une faible et transitoire restriction alimentaire, continuer à s'auto-priver d'aliments même si l'aliment est fourni ensuite ad libitum. La réponse est positive. En revanche, les R5-HT4 du NAc ne contribuent pas, à priori, à l'hypophagie due au stress. Puisque le système de la récompense est inclut dans celui de la prise de décision contrôlée par le cortex préfrontal médian (CPFm), nous avons supposé que l'effet hypophagique provoqué par le stress utilise les R5-HT4 corticaux. L'injection de traitements nucléiques (siRNA, virus), dans le CPFm de souris sauvages et privées des R5-HT4, montre que seule l'activation des R5-HT4 du CPFm est à l'origine de l'effet hypophagique du stress. Nos résultats suggèrent que [1] le stress active les R5-HT4 du CPFm et réduit la densité du transporteur de capture de la 5-HT, favorisant [2] l'augmentation du taux de la 5-HT extracellulaire dans le noyau d u raphé dorsal d'où, [3] un contrôle inhibiteur de l'activité des neurones 5-HT par le R5-HT1A permettant d'éviter que l'hypophagie ne se prolonge en conduite anorexigène. L'ensemble de nos résultats étayent la possibilité que le réseau neuronal de l'addiction et de la prise de décision de manger après stress inclut celui de la conduite anorexigène, avec jusqu'alors, une contribution évidente des R5-HT4. / To understand how the brain inhibits appetite despite an energy demand, we study the neuronal mechanisms, which underlie the hypophagic effect induced by the 3,4-N-methylenedioxymethamphetamine (MDMA: « Ecstasy ») and stress (forced immobilization) because these factors reduce appetite in animals, even starved. We show that stimulating serotonin 4 receptors (5-HTR4), or their overexpression (ectopic, physiological) in a brain reward area (nucleus accumbens: NAc), reduced hunger in increasing the appetite-suppressant effect of an addiction peptide: CART. Against the energy balance, the appetite-suppressant effect induced by stimulating 5-HTR4 in the NAc comes along with hyperactivity, often described in human suffering from anorexia nervosa. Supposing that a rewarding effect prevails over the danger of an energy imbalance, we show indeed that injecting 5-HTR4 antagonist in the NAc reduced the appetite-suppressant effect, the hyperactivity and the rewarding effect provoked by MDMA. If food deprivation is rewarding, mouse overexpressing 5-HTR4 in the NAc, after a low and transient diet period, should continue to self-imposed food refusal even in the presence of food ad libitum. The answer is positive. In contrast, 5-HTR4 in the NAc does not contribute, à priori, to stress-induced hypophagia. Because the reward system is included in the neuronal network of the decision-making, mainly controlled by the medial prefrontal cortex (mPFC), we postulated that hypophagia following stress uses cortical 5-HTR4. Injecting nucleic treatments (siRNA, virus), in the mPFC of wild-type or 5-HTR4 null mice, shows that only the stimulation of 5-HTR4 in the mPFC sparks off the hypophagic effect of stress. Our results suggest that [1] stress activates 5-HTR4 in the mPFC and reduces density of the 5-HT transporter, promoting [2] increase of the extracellular 5-HT level in the dorsal raphe nucleus and thus [3] an inhibitory control of t he activity of 5-HT neurons by 5-HTR1A allowing to avoid that the period of food restriction persists (anorexia-like behavior). Colectively, our findings support the the neuronal network of addiction and decision-making to eat after stress include the neuronal pathway related to anorexia, with so far, a clear contribution of 5-HTR4.

La contribution de la neurotransmission dopaminergique dans le noyau accumbens à l’effet de récompense induit par la stimulation électrique du cerveau a été l’objet de plusieurs années de recherche. Cependant, d’autres sites recevant des terminaisons dopaminergiques pourraient contribuer à moduler la récompense dans d’autres régions cérébrales. Parmi elles, on retrouve l’habenula qui reçoit des projections dopaminergiques de l’aire tegmentale ventrale. La contribution de cette voie au phénomène de récompense en général et à l’effet de recompense induit par l’autostimulation intracrânienne est peu connue. Le but de cette recherche était d’étudier la contribution de la dopamine mésohabenulaire à l’effet de recompense induit par la stimulation électrique du raphé dorsal. Des rats ont été implantés d’une bicanule dans l’Hb et d’une électrode dans le raphé dorsal. Le paradigme du déplacement de la courbe a été utilisé pour évaluer les changements dans l’effet de récompense à la suite de l’injection intra-habenulaire d’amphétamine (10-40 μg). À titre de contrôles positifs, des rats ont reçu l’amphétamine dans le core et dans le shell (1-20 μg) du noyau accumbens. Les injections d’amphétamine dans l’habenula n’ont pas changé l’effet de récompense induit par la stimulation électrique. Dans le noyau accumbens, les injections dans le shell et le core provoquent des augmentations dans l’effet de récompense comme il a déjà été démontré. Nos résultats suggèrent que la neurotransmission dopaminergique dans l’habenula latérale ne contribue pas significativement au circuit soutenant l’effet renforçant de la stimulation électrique du cerveau. / The contribution of nucleus accumbens dopamine neurotransmission to reward and reinforcement has been the focus of many years of study. Other terminal sites have received comparatively less research attention, but may be potentially important. One of these sites is the lateral habenula, which receives dopaminergic innervation from cells arising from the ventral tegmental area. Very little is known about the contribution of this pathway to reward in general and to the rewarding effect of electrical brain stimulation in particular. The goal of this study was to study the contribution of mesohabenular dopamine to reward induced by electrical stimulation of the dorsal raphe. Male Sprague-Dawley rats were implanted with bilateral cannulae in the lateral habenula and a stimulation electrode aimed at the dorsal raphe nucleus. Using the curveshift paradigm, we measured the rewarding effect of intra-habenular infusions of amphetamine (10-40 μg). Control rats received amphetamine infusions into nucleus accumbens core or shell subregions (1-20 μg). Our findings show that regardless of concentration, intra-habenular amphetamine did not alter brain stimulation reward. Infusions into the nucleus accumbens enhanced the rewarding effectiveness of the stimulation, as previously shown. Our findings suggest that dopaminergic neurotransmission within the lateral habenula does not contribute significantly to the circuitry that mediates the rewarding effect of electrical brain stimulation.

No description available.

Die These fasst die ersten Untersuchungen zum Pawlowsch`-Instrumentellen Transfer in alkoholabhängigen (AA) Patienten zusammen. Es ist bekannt, dass kontextuelle Umgebungsreize Verhalten beeinflussen. Tier- und Humanstudien haben gezeigt, dass positive Pawlowsche Reize instrumentelles Antwortverhalten verstärken und negative Pawlowsche Reize dieses reduzieren (PIT-Effekt). Bei Abhängigkeit wird angenommen, dass dieser Mechanismus relevant für Rückfall ist, da z.B. drogenassoziierte Reize bei Patienten im Vergleich zu Kontrollen erhöhtes Verlagen und funktionelle Aktivität in Belohnungsarealen auslösen. In Tier- und Humanstudien wurden stärkere PIT-Effekte vor allem mit funktioneller Aktivierung im Nucleus Accumbens (NAcc) beobachtet. Weiterhin zeigten sich bei Probanden mit stärkerem PIT-Effekt und bei AA Patienten erhöhte Impulsivitätswerte. Die PIT-Aufgabe besteht aus 3 Hauptteilen: i) Instrumentelle Konditionierung, ii) Pawlowsche Konditionierung, iii) Transfer mit Pawlowschen oder alkoholassoziierten Kontextstimuli. Impulsives Auswahlverhalten wurde durch die delay discounting Aufgabe erhoben. Es zeigten sich signifikant stärkere PIT-Effekte mit Pawlowschen Kontextreizen in AA Patienten im Vergleich zu Kontrollen mit funktioneller Aktivierung im NAcc, die zur Rückfallvorhersage beitrug. Der Transfer mit alkoholassoziierten Kontextreizen bewirkte eine signifikante Reduktion des instrumentellen Antwortverhaltens mit neuronalem Korrelat im NAcc nur bei abstinenten Patienten. Impulsives Auswahlverhalten und PIT hingen nur bei Patienten positiv zusammen. Die Studien lassen darauf schließen, dass PIT ein für Rückfall wichtiger Mechanismus ist mit funktionellem Korrelat im NAcc, der sich für motivationale Prozesse als auch als Salienzsignal relevant gezeigt hat. Die Subgruppe von hoch impulsiven Patienten ist im Besonderen durch Kontextreize im instrumentellen Antwortverhalten beeinflussbar, daher sollte ihr besondere Aufmerksamkeit bei Interventionen zukommen. / This thesis summarizes the first Pavlovian-to-instrumental transfer (PIT) studies in alcohol-dependent (AD) patients. Contextual stimuli are known to influence our behavior. Animal and human studies showed that positive Pavlovian stimuli enhance and negative Pavlovian stimuli reduce instrumental behavior (PIT effect). This mechanism might be relevant for relapse risk, as drug-associated stimuli have shown to enhance e.g. craving and functional activation in reward-related brain areas in patients compared to controls. In animal and human studies enhanced PIT effects were associated with activation particularly in the nucleus accumbens (NAcc). Moreover, control subjects with stronger PIT effects and AD patients were more impulsive on different facets of impulsivity. The PIT task consists of three main parts: i) instrumental conditioning, ii) Pavlovian conditioning, iii) transfer with Pavlovian background stimuli and instrumental task in the foreground (nondrug-related PIT: Pavlovian contextual cues; drug-related PIT: alcohol-related contextual cues). Choice impulsivity was measured by delay discounting task. We observed significantly enhanced nondrug-related PIT effects in AD patients compared to controls with a functional activation in the NAcc being predictive for relapse. Regarding drug-related PIT effects, we observed significantly reduced instrumental behavior during alcohol-related backgrounds with neural correlates in the NAcc in abstainers only. Choice impulsivity was positively related to PIT in AD patients only. Our data suggest that PIT is a mechanism contributing to relapse in AD patients with functional correlations within the NAcc, which based on our data is involved in motivation and attribution of salience. The subgroup of high impulsive patients is particularly susceptible for PIT effects, thus should be main target for intervention programs.

A dependência de drogas é um transtorno multifatorial complexo que se desenvolve em uma minoria de indivíduos que fazem uso dessas substâncias. Memórias associativas entre a droga e o contexto funcionam como gatilho para disparar comportamentos não adaptativos de busca e consumo, além de recaídas após períodos de abstinência. Subjacentes a essas mudanças comportamentais, existem modificações nas subunidades de receptores glutamatérgicos do tipo AMPA em estruturas envolvidas com memória (Hipocampo) e recompensa (Núcleo Accumbens). Por isso, estratégias que enfraqueçam a associação do contexto com a droga e que aprofundem o conhecimento dos circuitos envolvidos nesses comportamentos são de extrema relevância terapêutica. A memória quando evocada pode passar por dois processos pós-evocação: a extinção, em que uma nova memória é formada inibindo uma prévia associação, e a reconsolidação, em que a memória original entra em um estado lábil e suscetível a modificações, em que é possível enfraquecê-la através da inibição de sua reconsolidação. A reconsolidação da memória mostra-se uma estratégica mais eficaz e duradoura em relação à extinção, já que a memória original é modificada. Como modelo animal para o estudo da memória na dependência de drogas, o condicionamento de preferência por local (CPL) é bastante utilizado e sabe-se que é possível enfraquecer a preferência através do bloqueio da reconsolidação. Porém, são escassos os estudos que investigaram a existência da reconsolidação no modelo de sensibilização locomotora, que parece ocorrer, na maioria dos casos, em condição dependente do contexto de aquisição do comportamento, embora existam exemplos que demonstrem sua independência. As questões a serem respondidas neste trabalho são (a) se é possível reverter conjuntamente a preferência por local e a sensibilização locomotora à morfina (5 mg/kg) em ratos Wistar adultos machos, inibindo-se a síntese proteica com cicloheximida (CHX) i.p. logo após uma sessão de reativação contextual da memória no CPL, (b) se a reversão dos comportamentos reflete alterações (já descritas por outros autores) em GluA1, GluA1p (Ser845) e GluA2, no Hipocampo dorsal (HPCd) e no Núcleo Accumbens (NAc), e (c) se o mesmo tratamento em ambas estruturas reverte os dois parâmetros avaliados – comportamental e neuroquímico – de forma diferente ou igual. Nossos resultados mostraram ser possível reverter a preferência por local e a sensibilização locomotora por inibição sistêmica de síntese proteica, e que o condicionamento com exposição à morfina induz alterações nas subunidades analisadas de AMPA, conforme verificado no HPCd e NAc, embora a CHX não tenha produzido um efeito tão bem definido. Os animais que receberam infusões centrais no HPCd e NAc (central) não exibiram preferência por local, nem sensibilização. Em conjunto, nossos resultados mostraram, pela primeira vez em um mesmo desenho experimental, que é possível reverter diferentes aspectos da memória de recompensa (preferência e sensibilização) por meio do bloqueio da reconsolidação. / Drug addiction is a complex and multifactorial disorder that develops in a few people who use these substances. Associative memories between the drug and context of use act as a trigger for maladaptive behavior such as drug seeking and drug use, in addition to relapse after an extended period of withdrawal. Underlying these behavioral changes are modifications in glutamatergic reception (AMPA) in structures involved with memory (Hippocampus) and reward (Nucleus Accumbens). Therefore, strategies that weaken the drug and context association and deepen knowledge of circuits involved in these behaviors are extremely relevant therapeutically. When retrieved, a memory can undergo two distinct processes post-retrieval: extinction, in which a new memory inhibiting a previous association is generated, and reconsolidation, in which the original memory can enter a labile state and is susceptible to modifications, when it can be weakened by inhibition of its reconsolidation. Reconsolidation of memory has been shown to be a more effective and long lasting strategy in relation to extinction, since the original memory is modified. An animal model for studying drug addiction, conditioned place preference (CPP) is largely used and it is well known that it is possible to weaken preference by disrupting reconsolidation. However, there are few studies that investigate the existence of reconsolidation in a locomotor sensitization paradigm, which seems to occur in a condition dependent on context of acquisition, although some works report its independence. The questions answered in this work were (a) if it is possible to reverse both, context preference and locomotor sensitization to morphine (5mg/kg) by protein synthesis inhibition (CHX) after a contextual memory reactivation session in CPP, (b) if the disruption of behaviors reflects a reversal of changes of GluA1, GluA1p (Ser845) e GluA2 in dorsal Hippocampus (dHPC) and Nucleus Accumbens (NAc) and (c) if the same treatment in these structures differentially reverts the two parameters assessed. Our results indicate that it is possible to revert context preference and locomotor sensitization via systemic disruption of protein synthesis and that morphine conditioning induces changes in AMPA subunits in dHPC and NAc, although CHX did not have an evident effect on molecular reversal. Animals cannulated in dHPC and NAc core did not induce preference or sensitization. Taken together, our results demonstrated, for the first time, using the same experimental design that is possible to revert different aspects of reward memory (preference and sensitization) by disrupting the reconsolidation process.

L'impulsivité, un trait multidimensionnel, détermine la sévérité d'affections comportant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson, troubles obsessionnels compulsifs), mais la nature de la relation impulsivité / compulsivité reste méconnue. L'intérêt du présent travail est d'identifier les substrats neurobiologiques de la balance impulsivité / compulsivité, dans une approche transnosographique, en s'aidant au plan préclinique, de manipulations causales et au plan clinique, d'une approche corrélationnelle. Ainsi, nous démontrons pour la première fois en dehors du champ de l'addiction, non seulement que l'impulsivité motrice, endophénotype de vulnérabilité à la compulsivité, prédit, sous l'influence de la transmission noradrénergique, la transition vers la compulsivité, mais aussi que (dans le modèle de la maladie de Parkinson) la dénervation de la voie nigrostriée et les traitements substitutifs dopaminergiques amplifient l'état impulsif. D'où l'interaction complexe entre le trait impulsif, les traitements et le processus dégénératif. Enfin, nous démontrons le bénéfice thérapeutique de la stimulation de la portion antérieure du pallidum interne dans les formes sévères de tics et suggérons dans un modèle préclinique d'une grande valeur heuristique, que le trait impulsif prédit l'efficacité de la stimulation du core du noyau accumbens. Nos résultats démontrent l'intérêt de mieux caractériser le trait impulsif des patients présentant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson) et ouvrent ainsi de nouvelles perspectives thérapeutiques, tant pour la prévention de la transition de l'impulsivité à la compulsivité, que dans le traitement de ceux-ci. / Impulsivity, a multidimensional trait, determines the severity of compulsive disorders (Tourette's syndrome, Parkinson's disease, obsessive compulsive disorders), but the impulsive / compulsive relation remains unclear. The aim of this work is to identify the neurobiological substrates of impulsive / compulsive balance, using causal manipulations in rats and correlational studies in patients. The results demonstrate - for the first time beside the field of addiction - that, not only high impulsive trait is a transnosological endophenotype of increased vulnerability to develop compulsive disorders, but also that the transition from impulsivity toward compulsivity depends upon the noradrenergic transmission. Furthermore, we also show that, in a Parkinson's disease preclinical model, both the nigrostriatal denervation and dopaminergic treatments increase impulsive state, thereby indicating the contribution of a complex interaction between impulsive trait, medications and neurodegenerative process to the impulsive/compulsive balance. Finally, we show the therapeutic benefit of anterior globus pallidus interna in severe forms of tics and suggest in a preclinical model, with great heuristic value, that impulsive trait predicts the efficacy of nucleus accumbens core stimulation. Together, our results demonstrate the need to address the impulsive/compulsive balance in compulsive disorders and show promise for developing new pathophysiological-based therapeutic strategies that will treat both impulsivity and compulsivity.