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Thèse Nadège Morisot

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

Le 16 décembre 2013

Nadège Morisot soutiendra sa thèse le Lundi 16 décembre à 15h   (salle de réunion INCIA batiment 2A zone nord, 2e étage). Equipe "Neuropsychopharmacologie de l'Addiction" dirigée par Dr Martine Cador. Directeur de thèse: 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 Stressed cocaine-withdrawn mice show a genotype-independent higher c-fos mRNA expression in the perirhinal cortex, a brain region mediating NOR performance, than stressed drug-naïve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

Jury members

Dr. Daniel BERACOCHEA
DR CNRS (Bordeaux, France), President

Dr. Florence NOBLE
DR CNRS (Paris, France), Reviewer

Dr. Francesco PAPALEO
Chercheur (Genova, Italie), Reviewer

Dr Karine GUILLEM
CR CNRS (Bordeaux, France), Examinator

Dr. Mark J MILLAN
Responsable de recherches, Servier (Paris, France), Guest

Dr. Angelo CONTARINO
MCU (Bordeaux, France), Thesis supervisor

Directeur de thèse



Angelo Contarino
Maître de conférence - PhD
UFR Sciences pharmaceutiques U Bx 2 Segalen ; Université Bordeaux 2
CNRS UMR 5287 - INCIA
Institut de Neurosciences cognitives et intégratives d'Aquitaine
Université Victor Segalen Bordeaux 2
146 rue Léo Saignat
Bordeaux

Publications A.Contarino