Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol

Background: Central nicotinic cholinergic receptors modify alcohol-induced mesolimbic dopamine activation, which seems to be important in the reinforcing properties of alcohol. Consistent with this model, acute administration to rats of the tertiary nicotinic receptor antagonist mecamylamine blocks both alcohol consumption and alcohol-induced dopamine release in the nucleus accumbens. This study was conducted to test the hypothesis that, during the ascending limb of the blood alcohol concentration curve, mecamylamine would reduce the stimulating and pleasurable effects of an intoxicating dose of alcohol in humans. Methods: Ten female and 10 male volunteers with no history of alcohol or substance use disorders, including nicotine dependence, completed the study. During two laboratory sessions, subjects consumed three aliquots of an alcohol-containing drink, with a total ethanol content of 0.7 g/kg (in women) or 0.8 g/kg (in men), over a 30-min period. Two hours before the first drink, subjects were pretreated with mecamylamine or placebo, with the order of sessions counterbalanced. Primary outcome measures included the Drug Effect Questionnaire, the central stimulation subscale of the Alcohol Sensation Scale, and the stimulant subscale of the Biphasic Alcohol Effects Scale. Breath alcohol level (BAL) was examined to identify the ascending and descending limbs of the blood alcohol curve and to assess pharmacokinetic interactions between alcohol and mecamylamine. Results: Significant effects of time, study drug, and their interaction were observed. Compared with placebo, mecamylamine reduced BAL. After controlling for BAL at each time point, mecamylamine also reduced the Drug Effect Questionnaire and Alcohol Sensation Scale stimulant subscale scores, with a trend for a similar effect on the Biphasic Alcohol Effects Scale score. Conclusions: Mecamylamine seems to modify both the pharmacokinetic profile of alcohol and the rewarding effects of alcohol in healthy volunteers.