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La comorbidité entre dépendance aux opiacés et dépression : mécanismes sérotoninergiques dans un modèle murin

Abstract : Addiction is a chronic, frequent and serious brain disease, with relapse alternating with abstinence periods. Epidemiological studies show that abstinence, notably from opiates, is strongly associated with depression.Here we present the main clinical aspects of opiate addiction and depression, and most recent advances in molecular pathophysiology of both disorders. Then, we present our mouse model of opiate abstinence. Following chronic morphine exposure, depressive-like behaviours progressively emerge. Morphine treatment profoundly disrupts serotonergic signalling, notably in the dorsal raphe nucleus. In addition, behavioural deficits can be prevented by chronic treatment with fluoxetine, an antidepressant targeting serotonergic neurons. We then generalized our mouse model to heroin, another major illicit opiate. Using constitutive and conditional knockout strategies, we documented distinct roles for all 3 opioid receptors (mu, delta and kappa) in heroin abstinence. Finally, we initiated a large-scale analysis of transcriptomic regulations (mRNA and micro-RNA) occurring in our model as a function of heroin abstinence and fluoxetine treatment.These studies should reveal an unforeseen contribution of the dorsal raphe nucleus to addiction. They should uncover new molecular mechanisms underlying depressive-like behaviors in mice during opiate abstinence and thus put forward new therapeutic targets in humans.
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Pierre-Eric Lutz. La comorbidité entre dépendance aux opiacés et dépression : mécanismes sérotoninergiques dans un modèle murin. Neurobiologie. Université de Strasbourg, 2012. Français. ⟨NNT : 2012STRAJ022⟩. ⟨tel-00856593⟩

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