[Mechanism of withdrawal syndrome in alcohol dependence]

Abstract

Pathophysiological process of ethanol physical dependence and its withdrawal syndrome is supposed to result from adaptive changes in a number of neurotransmission systems, and several reports have demonstrated functional relationship between behavioral responses and neurotransmission systems in ethanol-dependent and -withdrawn animals. However, the molecular mechanisms underlying behavioral responses observed in these animals are still controversial at present. Alterations of beta-adrenergic receptor (beta-AR) function in the brains of mice physically dependent on ethanol were examined because of few available data on functional changes of beta-ARs and its significance in ethanol withdrawal signs. The protein level of beta-ARs also significantly increased in the frontal cortex of mouse with ethanol physical dependence and conditions withdrawn from ethanol after chronic treatment with ethanol vapor for 9 days. Intracerebroventricular administration of nadolol, a non-selective antagonist for beta-ARs, immediately after discontinuation of ethanol inhalation clearly attenuated the expression of withdrawal signs. These findings suggests that ethanol physical dependence induces beta-AR up-regulation, that is their increased number and facilitation of beta-AR signaling, which may at least in part participates in expression of tonic-clonic convulsion as one of ethanol withdrawal signs. We further investigated relationship between actin of cytoskeleton and relapse of alcohol dependence after withdrawal from alcohol vapor inhalation for 9 days. After 3 days of withdrawal from alcohol vapor alcohol-induced place preference was enhanced, which was blocked by the treatment with an actin polymerization inhibitor, cytochalasin D, and anactin depolymerization inhibitor, phalloidin, during 3 days after ethanol withdrawal. These findings suggest that changes in actin turnover on withdrawal from alcohol vapor involve in sensitization of alcohol-induced place preference.