Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (UMR5287)

Aquitaine Institute for Cognitive and Integrative Neuroscience



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Université de Bordeaux

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Home > Teams > ADDICTEAM (M. CADOR) > Thesis defense

Nadège Morisot Ph.D, 16th December 2013

by Catherine Le Moine - published on , updated on

The CRF2 receptor-deficiency reduces the cognitive and social deficits induced by cocaine

Nadège Morisot’s Ph.D defense,16th of December 2013

Ph.D director: Angelo Contarino

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 Stressed cocaine-withdrawn mice show a genotype-independent higher c-fos mRNA expression in the perirhinal cortex, a brain region mediating NOR performance, than stressed drug-naïve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.

Keywords : Corticotropin-releasing factor (CRF) system; CRF1 receptors; CRF2 receptors; null-mutant mice; Cocaine; Novel object recognition; Memory; Sociability; Social novelty preference; Emotion; Vulnerability ; Stress.

Publications

The CRF2 receptor mediates social breakdown induced by cocaine N. Morisot, M.J. Millan & A. Contarino, in preparation

The CRF2 receptor mediates cognitive vulnerability induced by cocaine N. Morisot, M.J. Millan & A. Contarino, in preparation

Dissociation of recognition memory and anxiety-like effects of cocaine in CRF1 receptor-deficient mice N. Morisot, M.J. Millan & A. Contarino, submitted

Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine N.E. Clifton, N. Morisot, M.J. Millan, F. Loiseau (2013) Psychopharmacology (Berl), 225, 579-594

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