Varenicline, a partial agonist at neuronal nicotinic acetylcholine receptors, reduces nicotine-induced increases in 20% ethanol operant self-administration in Sprague-Dawley rats

Abstract

Alcohol and nicotine use disorders are often treated as separate diseases, despite evidence that approximately 80-90% of alcohol dependent individuals are also heavy smokers. Both nicotine and ethanol have been shown to interact with neuronal nicotinic acetylcholine receptors (nAChRs), suggesting these receptors are a common biological target for the effects of nicotine and ethanol in the brain. There are few studies that have examined the effects of co-administered nicotine and ethanol on the activity of nAChRs in rodents. In the present study, we show that Sprague-Dawley rats, a strain often used for nicotine studies but not as often for voluntary ethanol intake studies, will consume 20% ethanol using both the intermittent-access two-bottle-choice and operant self-administration models without the need for sucrose fading. We show that nicotine (0.2 mg/kg and 0.8 mg/kg, s.c.) significantly increases operant 20% ethanol self-administration and varenicline (2 mg/kg, s.c), a partial agonist at nAChRs, significantly decreases operant ethanol self-administration and nicotine-induced increases in ethanol self-administration. This suggests that nAChRs play an important role in increasing ethanol self-administration and that varenicline may be an efficacious treatment for alcohol and nicotine co-dependencies.

Figure 1

High ethanol consumption in Sprague Dawley Rats using the intermittent access 20% ethanol two-bottle choice paradigm. (A.) Ethanol consumption (g/kg) was significantly greater for SD rats following intermittent-access 20% ethanol compared to continuous-access 10% ethanol with a sucrose fade. The values are expressed as the mean ethanol intake (g/kg/24hr) ± SEM (two-way ANOVA followed by Newman-Keuls post hoc test). The amount of ethanol consumed significantly correlated with the measured blood ethanol concentrations BECs: intermittent 20% ethanol (B.): r²=0.7607, p<0.001; continuous 10% ethanol (C.): r²=0.6782, p < 0.05. Blood Ethanol Concentrations (BECs, mg/dl) for each animal were measured following 30 minutes of voluntary oral ethanol access using either intermittent access or continuous access protocols. * p< 0.05, ** p<0.01, *** p<0.001, n=31 for the 20% ethanol group and n=10 for the 10% ethanol group.

Figure 2

SD rats self-administer 20% ethanol using an operant self-administration paradigm. (A.) Animals that were previously exposed to the intermittent-access, 20% ethanol two-bottle choice model (n=23) exhibited significantly higher intake levels in comparison to animals that were previously exposed to 10% ethanol (n=9). The values are expressed as the mean ethanol intake (g/kg/24hr) ± SEM (two-way ANOVA followed by Newman-Keuls post hoc test). Blood samples were collected from the lateral tail vein immediately following the 30-minute FR3 session for BEC determination. The amount of ethanol consumed for the 20% ethanol- and 10% ethanol-responding animals significantly correlated with the measured BECs (linear regression): 20% ethanol (B.): r²=0.6667, p<0.001; 10% ethanol (C.): r²=0.4782, p < 0.05. * p< 0.05, ** p<0.01, *** p<0.001, n=23 for the 20% ethanol group and n=9 for the 10% ethanol group.

Figure 3

Nicotine administration increases 20% ethanol operant self-administration. (A.) Nicotine (0.8 mg/kg, s.c.), but not vehicle (saline), administered 15 minutes prior to the session significantly increases ethanol intake. The values are expressed as mean ethanol intake g/kg/60min ± SEM (two-way ANOVA followed by Newman-Keuls post hoc test). * p< 0.05, ** p<0.01, *** p<0.001, n=12 for the nicotine group and n=11 for the vehicle group.

Figure 4

Varenicline significantly decreases nicotine induced increases in 20% ethanol operant self-administration in SD rats. Varenicline (2 mg/kg s.c.) was administered 30 minutes prior to nicotine (0.8 mg/kg s.c that was administered 15 mins prior to the operant session. The values are expressed as mean ethanol consumed (g/kg/60 min) ± SEM (two-way repeated measures ANOVA followed by Newman-Keuls post hoc test). * p<0.05, *** p<0.001 compared to varenicline vehicle within treatment group, n = 11 to 12 per group.