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

Aquitaine Institute for Cognitive and Integrative Neuroscience

Université de Bordeaux

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

Khalid Rouibi’s Ph.D, December 21st 2011

by Catherine Le Moine - published on , updated on

Opiate illicit use represents one of the most severe sanitary problems throughout the world. Among humans, the emergence of the opiate withdrawal (OW) syndrome after cessation of opiate intake is considered as one of the key motivational elements that lead to the vulnerability to opiates relapse. Therefore, the OW is characterized by a various alterations of the behavioral and neurobiological homeostasis responses to stress which are determinants in opiate dependence. The Corticotropin-releasing factor (CRF) system is the major coordinator of stress-responsive circuitry. Through its two receptors CRF1 and CRF2, the CRF system has recently emerged as major contributor in the development of components of the OW syndrome. The aim of this thesis is to determine the role of CRF2 receptor in the negative affective states and motivational disorders implicated in opiate relapse during OW.
Behavioral and biological experiments were conducted in CRF2 receptor-deficient mice (CRF2-/-). We reported that genetic deletion of the CRF2 receptor eliminates dysphoria and molecular alterations elicited by OW without impairing brain, neuroendocrine and autonomic stress-coping responses to withdrawal. Using behavioral approaches of operant responding to highly palatable food (HPF) we found that CRF2-/- reduces motivational disorders induced by intermittent morphine injections and withdrawal. Finally, we described a mouse model of stress-induced food reinstatement seeking behavior during prolonged OW. Furthermore, we reported a gender dimorphism in the role of the CRF2 receptor in the stress-induced reinstatement of HPF seeking behavior long-lasing after opiate treatment.
These findings underscore the importance of CRF2 receptor as possible effective treatment of the critical problem of opiate dependence.

Keywords: Opiate dependence; Corticotropin releasing factor system; CRF2 receptor pathway; withdrawal; negative affect; anhedonia; motivation; relapse; stress; mouse

Mr SIMMONET, Guy (PU, Bordeaux, Président)
Mme NOBLE, Florence (PU, Paris, Rapporteur)
Mme DAUGÉ, Valérie (MC, Paris, Rapporteur)
Mme CADOR, Martine (Dr, Bordeaux, Examinateur
Mr AHMED Serge (Dr, Bordeaux, Examinateur
Mr CONTARINO, Angelo (MC, Bordeaux, Directeur de thèse)