Le stress prenatal augmente la vulnerabilIte a certames substances d abus chez le rat. L objectif de cette thèse était de déterminer si un stress subit in utero pouvait moduler durablement la vulnérabilité à l'éthanol. Deux aspects de Ia vulnérabilité ont été explorés: 1) la sensibilité aux effets produits par une administration d'éthanol: 2) la propension à consommer cette substance. Comparés aux témoins, les animaux adolescents stressés étaient moins sensibles aux effets d'une injection d'éthanol au niveau hormonal (activation de l'axe c0l1icotrope) et neurobiologique (activation des défenses anti¬oxydantes dans l'hippocampe). Une alcoolisation chronique avait un effet délétère sur la mémoire des rats témoins. mais de façon surprenante améliorait les performances mnésiques des stressés. Ces effets pourraient être sous-tendus par les modulations opposées des récepteurs mGlu observées dans l'hippocampe après l'alcoolisation. Chez des animaux mâles isolés (1 rat par cage), le stress prénatal n'altérait pas la préférence pour l'éthanol Cependant. un traitement chronique à l'éthanol augmentait spécifiquement chez les animaux stressés les quantités de [Delta]FosB (un facteur de transcription impliqué dans la vulnérabilité à la consommation de drogues) dans le noyau accumbens. Chez des femelles adolescentes, les conditions d'élevage (rats isolés ou par paires) modulaient différemment la consommation d'alcool des stressées et témoins. Ces données indiquent que le stress prénatal modifie durablement la vulnérabilité à l'éthanol chez le rat et soulignent l'importance de prendre en compte l'histoire de l'individu. même très précoce. pour appréhender la genèse des conduites addictives. / In rats, exposure to prenatal stress leads to a greater vulnerabiliy to several drugs of abuse (i.e. psychostimulants and opiates). The aim of the present work was to examine the impact of a prenatal stress (restraint stress of the pregnant dam) on ethanol vulnerability in adolescent and adult rats. Two distinct aspects of the vulnerability were evaluated : 1) the individual differences in the ethanol sensitivity: 2) the spontaneous consumption of ethanol Prenatally stressed rats were less sensitive than control rats to the effects of an ethanol injection during adolescence at the hormonal (HPA. axis activation) and neural (antioxidant defences in the hippocampus) levels. A chronic ethanol treatment induces memory impairments in control rats, whereas it has a beneficial effect on memory in rat subjected to a prenatal stress. These opposite effects could be mediated by the differential modulation of metabotropic glutamate receptors' levels in the hippocampus reported after the ethanol exposure. Prenatal stress has no impact on ethanol preference in isolated male rats. However. a chronic êlhanol treatment increased selectively the [Delta]FosB levels. a transcription factor involved in the vulnerability to drugs consumption, in the nucleus accumbens of prenatally stressed rats. Finally, we observed in female rats interplay between prenatal stress and rearing conditions on the ethanol consumption. Together, these data indicate that prenatal stress, in interaction with other experimental factors, can affect the ethanol sensitivity and consumption. They stress the importance to consider early life events in the study of the addictive behaviour genesis.

Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access "binge" cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.

<p>Obsessive-compulsive disorder (OCD) is a devastating illness that afflicts around 2% of the world's population with recurrent distressing thoughts (obsessions) and repetitive ritualistic behaviors (compulsions). While dysfunction at excitatory glutaminergic excitatory synapses leading to hyperactivity of the orbitofrontal cortex and head of the caudate - brain regions involved in reinforcement learning - are implicated in the pathology of OCD, clinical studies involving patients are unable to dissect the molecular mechanisms underlying this cortico-striatal circuitry defect. Since OCD is highly heritable, recent studies using mutant mouse models have shed light on the cellular pathology mediating OCD symptoms. These studies point toward a crucial role for deltaFosB, a persistent transcription factor that accumulates with chronic neuronal activity and is involved in various diseases of the striatum. Furthermore, elevated deltaFosB levels results in the transcriptional upregulation of Grin2b, which codes GluN2B, an N-methyl-D-aspartate glutamate receptor (NMDAR) subunit required for the formation and maintenance of silent synapses. Taken together, the current evidence indicates that deltaFosB-mediated expression of aberrant silent synapses in caudate medium spiny neurons (MSNs), in particular D1 dopamine-receptor expressing MSNs (D1 MSNs), mediates the defective cortico-striatal synaptic transmission that underlies compulsive behavior in OCD.</p> / Dissertation