Lack of stimulant and anxiolytic-like effects of ethanol and accelerated development of ethanol dependence in mu-opioid receptor knockout mice

The opioid system is implicated in various aspects of alcoholism. Acute ethanol administration produces anxiolytic-like effects in rodents while alcohol withdrawal induces anxiogenic-like effects. Mice lacking the mu-opioid receptor (MOR) do not self-administer ethanol and display decreased anxiety-like behavior. We hypothesized that MOR might be involved in the development and expression of alcoholism, particularly in relation to anxiety states. In mice lacking MOR (MOR−/− mice), we examined the acute anxiolytic-like and locomotor stimulant effects of ethanol (0, 0.75, 1.25, 1.75 g/kg, i.p.). In a separate experiment, mice were submitted to chronic ethanol-containing liquid diet and we assessed somatic and affective ethanol withdrawal on three consecutive withdrawal episodes by scoring handling-induced convulsions and anxiety-like behavior. Deletion of MOR blocked the acute anxiolytic-like and stimulant effects of ethanol. Furthermore, MOR−/− mice displayed affective and physical signs of ethanol withdrawal in earlier withdrawal tests than wild-type mice. The present results implicate MOR in affective and somatic aspects of ethanol exposure and withdrawal. In addition, our findings support the hypothesis that the clinical efficacy of the opioid receptor antagonist naltrexone against relapse to alcoholism might be related to an action on the acute positive effects of alcohol rather than the negative affect of abstinence.