Reduction of spontaneous alcohol drinking and physical withdrawal by levemopamil, a novel Ca 2+ channel antagonist, in rats

Abstract

Neuronal Ca 2+ channels have been shown to be involved in both alcohol drinking behavior in rats and nonhuman primates and in the manifestation of alcohol withdrawal symptoms in rodents. Experiments were performed to determine the effect of a single injection of levemopamil, a novel Ca 2+ channel antagonist with antiserotonergic [5-hydroxytryptamine 2 (5-HT 2)] properties, on alcohol preference and alcohol withdrawal symptoms in alcohol-preferring (P) and Wistar rats, respectively. P rats were individually housed and provided free access to food, water, and a solution of 10% (v/v) ethanol. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline, P rats were injected with levemopamil (0, 3.3, 10, 15, and 20 mg/kg) and their food, water, and alcohol intakes measured 24 h later. In a separate experiment, the ability of acute and chronic (12 consecutive days) administrations of levemopamil to suppress alcohol withdrawal symptoms in chronically alcohol-treated rats was studied. In addition, the effects of levemopamil on the level of monoamines in different areas of the brain, as well as its action in alcohol metabolism, were examined. Our findings showed that a single administration of levemopamil (10, 15, and 20 mg/kg) significantly and dose-dependently attenuated alcohol intake and increased water intake in P rats. Both acute and chronic treatment with levemopamil reduced the alcohol withdrawal symptoms, overall seizure scores, and proportion of rats seizing. A single injection of levemopamil produced a clear, but not significant, trend to increase the 5-HT turnover rate in certain brain areas. This drug did not influence the pharmacokinetics of alcohol. Our results show that levemopamil exerts an inhibitory action on alcohol preference in alcohol-preferring rats and suppresses alcohol withdrawal symptoms in chronically alcohol-treated rats. Although the mechanism(s) of action is not fully understood, it is likely that levemopamil exerts its action by interfering with either neuronal Ca 2+ channels and/or serotonergic systems, particularly 5-HT 2 receptors.