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Thèse Alessandro PICCIN

Role of the CRF system in the rewarding and motivational effects of morphine

Le 18 décembre 2018

Date de la soutenance: salle de conférence CGFB (Bordeaux), 18/12/2018 à 15:00 . Directeur de thèse: Angelo Contarino de l'INCIA team leader: "Searching targets to regulate stress systems"


 Opiate use disorders (OUDs) are chronic relapsing diseases with a major health and socio-economic impact.
Like other substance use disorders, OUDs are characterized by a myriad of somatic, emotional-like, motivational, cognitive and social behavior deficits. Nevertheless, the brain mechanisms underlying their clinical features remain poorly understood, hampering the development of novel effective therapies. The corticotropin-releasing factor (CRF) system, a major coordinator of behavioral, neuroendocrine and autonomic responses to stressors, might play a critical role in behavioral and brain alterations associated with OUDs. CRF-like peptides exert their actions through two subtypes of receptors, termed CRF1 and CRF2. Using clinically-oriented laboratory animal models, previous studies reported differential, and often opposite, roles for the two CRF receptor subtypes in the effects of substances of abuse. For instance, genetic inactivation of CRF1 or CRF2 receptors respectively exacerbated or reduced somatic signs and cognitive deficits associated with relatively early or late opiate withdrawal phases. However, the role of the CRF system in the social behavior deficits induced by opiate administration and withdrawal remains largely unknown.

In the current work, we employed the three-chamber (3-CH) task to assess the impact of chronic morphine administration and withdrawal upon social behavior in mice. Surprisingly, we found that morphine withdrawal increased, instead of decreasing, the social interest towards an unfamiliar same-sex conspecific in male mice. Further ethological analyses revealed that morphine withdrawal increased aggressive behavior as well. Notably, social interest and aggressive behavior followed a similar time-course and positively correlated with one another, suggesting a major role for aggressiveness in the apparent social interest displayed by opiate-withdrawn mice. The latter findings indicate that aggressive behavior might contribute to the social behavior dysfunctions associated with substance withdrawal.

In addition, exposure to an ethological environmental stressor relatively long time after morphine discontinuation did not affect social behavior, indicating stress resilience in opiate-withdrawn mice. Finally, using the CRF1 receptor-deficient mouse model, we also investigated the role of the CRF1 receptor in the effects of opiate withdrawal upon social behavior. We found that CRF1 receptor-deficiency increased social interest in substance-naïve male mice. Moreover, like the study mentioned above, we found that opiate withdrawal increased the interest for an unfamiliar conspecific as well, strengthening the notion of aggressive-driven social approach in opiate-withdrawn male mice. Drugs of abuse activate brain reward systems and strongly narrow behavior towards substance-seeking and -taking to the detriment of “natural” rewards, such as social interaction and food intake. Thus, using the conditioned place preference (CPP), the 3-CH and the operant behavior paradigms, we assessed morphine effects upon brain reward, social behavior and motivation for food. We found that a single, acute administration of a relatively low morphine dose induced CPP, indicating activation of brain reward systems.
However, the same drug dose strongly impaired social behavior and motivation for food in both male and female mice. Notably, morphine did not affect ambulation, olfaction or anxiety-like behavior, suggesting a selective substance-induced disruption of the rewarding and motivational properties of social behavior and food intake. Altogether, our findings indicate that, independently from the gender, administration of a small, brain-rewarding dose of morphine strongly decreases the interest for “natural” rewards in mice, providing initial experimental evidence of “hijacking” of brain reward systems by substances of abuse. At last, to investigate the role of the CRF system in vulnerability of brain reward and motivation systems to opiate substances, we used the CRF1 receptor-preferring antagonist antalarmin. Systemic administration of the compound fully rescued the deficits in social interest, but did not affect the reduced motivation for food induced by morphine.
Thus, at least to some extent, the latter results indicate a critical role for the CRF system in substance-induced decreased interest for “natural” rewards, strengthening the notion of a therapeutic potential for CRF-targeting pharmacological agents.

 Key-words: mice; social behavior; motivation; natural rewards; food; drugs of abuse; morphine; opiate withdrawal; vulnerability; stress; aggressive behavior; corticotropin-releasing factor; pharmacology.

Publications:

"Increased social interest and aggressive behavior in opiate-withdrawn mice." A. Piccin, G. Courtand, A. Contarino - IN PREPARATION

"CRF1 receptor-deficiency increases social interest in mice." A. Piccin, A. Contarino - IN PREPARATION

"Morphine decreases the motivation for social behavior and palatable food in mice: role of the CRF system." A. Piccin, A. Contarino - IN PREPARATION

 "Gender-dependent alterations in social behavior in CRF2 receptor-deficient mice." A. Piccin, A. Contarino - IN PREPARATION

Jury

Dr. Angelo Contarino,
MCU Directeur de thèse,
Université de Bordeaux
Dr. Véronique Deroche-Gamonet
Président du jury,
Université de Bordeaux
Dr. Florence Noble
Rapporteur, Université Paris Descartes
Dr. Marcello Solinas
Rapporteur, Université de Poitiers