Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract

Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.

Fig. 1.

Varenicline decreased ethanol but not sucrose seeking. Varenicline (0.3–2 mg/kg s.c.) was administered 30 min before the start of the session. One and 2 mg/kg significantly and dose-dependently inhibited active lever presses for 10% ethanol (A) but not 5% sucrose (B). The values are expressed as mean no. of active lever presses ± SEM (repeated measures ANOVA followed by Newman–Keuls post hoc test). *, P < 0.05; **, P < 0.01 compared with vehicle, n = 7–8.

Fig. 2.

Naltrexone decreases both ethanol and sucrose seeking. Naltrexone (1 mg/kg s.c.) administered 30 min before the start of the session significantly inhibits active lever pressing for both 10% ethanol (A) and 5% sucrose (B). The values are expressed as mean no. of active lever presses ± SEM (paired Student's t test). *, P < 0.05; **, P < 0.01 compared with vehicle, n = 7–8.

Fig. 3.

Varenicline significantly decreased ethanol consumption in rats that chronically consume low to moderate amounts of ethanol (continuous access to 10% ethanol). Varenicline (0.3–2 mg/kg s.c.) was administered 30 min before the start of the drinking session. Varenicline (1 and 2 mg/kg) significantly decreased ethanol consumption 30 min (A) and 6 h (B) after the onset of drinking. The values are expressed as mean ethanol consumed (g/kg) ± SEM (repeated-measures ANOVA followed by Newman–Keuls post hoc test). *, P < 0.05; **, P < 0.01 compared with vehicle, n = 7.

Fig. 4.

Varenicline significantly decreases ethanol consumption in rats chronically consuming large amounts of ethanol (intermittent access to 20% ethanol). Varenicline (0.3–2 mg/kg s.c.) was administered 30 min before the start of the drinking session. Varenicline (1 and 2 mg/kg) significantly decreased ethanol consumption 30 min (A) and 6 h (B) after the onset of drinking. The values are expressed as mean ethanol consumed (g/kg) ± SEM (repeated measures ANOVA followed by Newman–Keuls post hoc test). **, P < 0.01; ***, P < 0.001 compared with vehicle, n = 8.

Fig. 5.

Chronic administration of varenicline significantly decreases ethanol consumption in rats chronically consuming ethanol (intermittent access to 20% ethanol). Varenicline (2 mg/kg s.c.) or vehicle was administered to two different groups of rats on each of 6 consecutive days, 30 min before the start of the ethanol- or water-drinking session. The effect of varenicline or vehicle on ethanol consumption was measured on days 1, 3, and 6 and compared with baseline drinking levels. Varenicline but not vehicle administration significantly decreased ethanol consumption (g/kg) compared with baseline drinking levels at 30 min (A) and 6 h (B) after the onset of drinking. Vehicle administration had no significant effect on the ethanol consumption compared with baseline drinking levels at 30 min (A) or 6 h (B) after the onset of drinking. There was no difference between baseline and posttreatment baseline drinking levels within either the varenicline or vehicle group, respectively (A and B). The values are expressed as mean ± SEM (repeated-measures ANOVA within each treatment group followed by Newman–Keuls post hoc test). **, P < 0.01; ***, P < 0.001 compared with baseline drinking levels, n = 5.