La délétion génétique du récepteur corticotropin-releasing factor de type 2 réduit les déficits mnésiques et sociaux induits par la cocaïne

MORISOT, Nadège

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MORISOT, Nadège

Language

Thèses de doctorat

Date

2013-12-16

Speciality

Neurosciences

Doctoral school

École doctorale Sciences de la vie et de la santé (Bordeaux)

Abstract

Les travaux de cette thèse visent à étudier le role du système corticotropin-releasing factor (CRF) dans les dysfonctions cognitives, les altérations du comportement social et la vulnérabilité au stress associées à l’addiction aux drogues. Les effets de la délétion génétique du récepteur CRF1 ou CRF2 sont examinés dans les tests de reconnaissance d’objet et de préférence sociale après une exposition chronique et pendant le sevrage à la cocaine. Le rôle du récepteur CRF2 dans la vulnérabilité au stress qui pourrait précipiter l’apparition de déficits cognitifs et sociaux pendant le sevrage prolongé à la cocaine est également étudié.Read less <

English Abstract

Stimulant-related disorders are characterized by emotional-like, cognitive and social dysfunction that may contribute to the maintenance of the disease. In addition, stimulant use and withdrawal may alter brain stress systems. The corticotropin-releasing factor (CRF) system is a major stress coordinator hypothesized to contribute to substance-related disorders. CRF signalling is mediated by two receptor types, named CRF1 and CRF2. The specific role of each of the CRF receptors in negative affective-like, cognitive and social dysfunction associated with stimulant administration and withdrawal remains largely unknown. The present study demonstrates that the CRF1 receptor-deficiency increases the anxiety-like behaviour induced by intermittent administration of escalating doses of cocaine (5-20 mg/kg, i.p.), as assessed by the elevated plus maze. In addition, the same cocaine regimen induces novel object recognition (NOR) and sociability deficits, which are unaffected by CRF2 receptor-deficiency. However, CRF2 receptor-deficiency effectively shortens the duration of the NOR and sociability deficit induced by cocaine withdrawal. Furthermore, following the apparent recovery of NOR and sociability performances during relative long-term (42 days) cocaine withdrawal, CRF2 receptor-deficiency eliminates the stress-induced re-emergence of NOR and sociability deficit. Stressed cocaine-withdrawn mice show a genotype-independent higher c-fos mRNA expression in the perirhinal cortex, a brain region mediating NOR performance, than stressed drug-naïve mice. However, neither genotype nor drug withdrawal affects the expression of tyrosine hydroxylase in the ventral tegmentale area and the locus coeruleus, CRF in the amygdala and the paraventricular nucleus of the hypothalamus and dynorphin in the nucleus accumbens shell. The latter results suggest that stress vulnerability during long-term cocaine withdrawal is not due to alterations in stress-coping mechanisms. The present study provides initial evidence of a critical role for the CRF system in cognitive and sociability deficits and vulnerability induced by stimulant administration and withdrawal, suggesting new therapeutic strategies for substance-related disorders.Read less <

Keywords

Système corticotropin-releasing factor (CRF)

Récepteurs CRF1

Récepteurs CRF2

Cocaïne

Mémoire

Emotion

Sociabilité

Vulnérabilité

Stress

Génétique délétion

Souris

English Keywords

Corticotropin-releasing factor (CRF) system

CRF1 receptors

CRF2 receptor

Cocaine

Memory

Emotion

Sociability

Vulnerability

Stress

Genetic deletion

Mouse

Mice

URI

https://oskar-bordeaux.fr/handle/20.500.12278/22135

Origin

STAR imported

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