Effects of varenicline on ethanol-induced conditioned place preference, locomotor stimulation, and sensitization

Varenicline, a partial nicotinic acetylcholine receptor (nAChR) agonist, is a promising new drug for the treatment of alcohol (ethanol [EtOH]) dependence. Varenicline has been approved by the Food and Drug Administration as a smoking cessation therapeutic and has also been found to reduce EtOH consumption in humans and animal models of alcohol use. These studies examined the hypotheses that varenicline attenuates the stimulant and sensitizing effects of EtOH and reduces the motivational effects of EtOH-associated cues. The goal was to determine whether these effects of varenicline contribute to its pharmacotherapeutic effects for alcohol dependence. In addition, effects of varenicline on acute stimulation and/or on the acquisition of sensitization would suggest a role for nAChR involvement in these effects of EtOH. Methods: Dose-dependent effects of varenicline on the expression of EtOH-induced conditioned place preference (CPP), locomotor activation, and behavioral sensitization were examined. These measures model motivational effects of EtOH-associated cues, euphoric or stimulatory effects of EtOH, and EtOH-induced neuroadaptation. All studies used DBA/2J mice, an inbred strain with high sensitivity to these EtOH-related effects. Results: Varenicline did not significantly attenuate the expression of EtOH-induced CPP. Varenicline reduced locomotor activity and had the most pronounced effect in the presence of EtOH, with the largest effect on acute EtOH-induced locomotor stimulation and a trend for varenicline to attenuate the expression of EtOH-induced sensitization. Conclusions: Because varenicline did not attenuate the expression of EtOH-induced CPP, it may not be effective at reducing the motivational effects of EtOH-associated cues. This outcome suggests that reductions in the motivational effects of EtOH-associated cues may not be involved in how varenicline reduces EtOH consumption. However, varenicline did have effects on locomotor behavior and significantly attenuated acute EtOH-induced locomotor stimulation. In humans who drink while taking varenicline, it might similarly reduce stimulant responses and have an impact on continued drinking. General sedative effects in such individuals should be carefully considered.