Distinct mu, delta, and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence.
Fiche publication
Date publication
octobre 2014
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Auteurs
Membres identifiés du Cancéropôle Est :
Mme KOEBEL Pascale, Dr LUTZ Pierre-Eric, Dr BEFORT Katia
Tous les auteurs :
Lutz PE, Ayranci G, Chu-Sin-Chung P, Matifas A, Koebel P, Filliol D, Befort K, Ouagazzal AM, Kieffer BL
Lien Pubmed
Résumé
Addiction is a chronic disorder involving recurring intoxication, withdrawal, and craving episodes. Escaping this vicious cycle requires maintenance of abstinence for extended periods of time and is a true challenge for addicted individuals. The emergence of depressive symptoms, including social withdrawal, is considered a main cause for relapse, but underlying mechanisms are poorly understood. Here we establish a mouse model of protracted abstinence to heroin, a major abused opiate, where both emotional and working memory deficits unfold. We show that delta and kappa opioid receptor (DOR and KOR, respectively) knockout mice develop either stronger or reduced emotional disruption during heroin abstinence, establishing DOR and KOR activities as protective and vulnerability factors, respectively, that regulate the severity of abstinence. Further, we found that chronic treatment with the antidepressant drug fluoxetine prevents emergence of low sociability, with no impact on the working memory deficit, implicating serotonergic mechanisms predominantly in emotional aspects of abstinence symptoms. Finally, targeting the main serotonergic brain structure, we show that gene knockout of mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) before heroin exposure abolishes the development of social withdrawal. This is the first result demonstrating that intermittent chronic MOR activation at the level of DRN represents an essential mechanism contributing to low sociability during protracted heroin abstinence. Altogether, our findings reveal crucial and distinct roles for all three opioid receptors in the development of emotional alterations that follow a history of heroin exposure and open the way towards understanding opioid system-mediated serotonin homeostasis in heroin abuse.
Mots clés
Animals, Antidepressive Agents, Second-Generation, pharmacology, Depression, metabolism, Disease Models, Animal, Dorsal Raphe Nucleus, drug effects, Fluoxetine, pharmacology, Heroin, pharmacology, Heroin Dependence, physiopathology, Male, Memory Disorders, physiopathology, Memory, Short-Term, drug effects, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Narcotics, pharmacology, Receptors, Opioid, kappa, genetics, Receptors, Opioid, mu, genetics, Social Behavior, Spatial Memory, drug effects, Substance Withdrawal Syndrome, drug therapy
Référence
Neuropsychopharmacology. 2014 Oct;39(11):2694-705