The role of varenicline on alcohol-primed self-administration and seeking behavior in rats

Abstract

Rationale: Varenicline, a smoking-cessation agent, may be useful in treating alcohol use disorders. An important consideration when studying factors that influence drinking/relapse is influence of the pharmacological effects of alcohol on these behaviors. Pre-exposure to alcohol (priming) can increase craving, drinking, and seeking behaviors.

Objectives: The primary goal of this work was to determine the effects of varenicline on alcohol-primed self-administration and seeking behavior in male Long-Evans rats.

Methods: First, we assessed whether varenicline (0, 0.3, 1, 3 mg/kg, IP) has alcohol-like discriminative stimulus effects and whether varenicline alters sensitivity to alcohol in rats trained to discriminate a moderate alcohol dose (1 g/kg, IG) vs. water. Second, animals trained to self-administer alcohol underwent assessments to test the effects of: (i) varenicline (0, 0.3, 1, 3 mg/kg, IP) on self-administration, (ii) alcohol priming (0, 0.3, 1 g/kg, IG) on self-administration and seeking behavior, and (iii) varenicline (1 mg/kg) in combination with alcohol priming (1 g/kg) on these behaviors.

Results: Varenicline did not substitute for alcohol but disrupted the expression of sensitivity to alcohol. Varenicline decreased self-administration but only at a motor-impairing dose (3 mg/kg). Alcohol priming decreased self-administration and seeking behavior. Varenicline (1 mg/kg) blocked this effect under self-administration conditions, but not seeking conditions, which effectively resulted in increased alcohol intake.

Conclusions: These findings suggest the importance of further behavioral and mechanistic studies to evaluate the use of varenicline in treating alcohol use disorders and its potential impact on drinking patterns in smokers using varenicline as a smoking-cessation aid.

Figure 1

The experimental design and timeline for the experiments showing training history for the self-administration (SA) experiments and within group testing. The three separate timelines represent different group of rats.

Figure 2

Discriminative stimulus effect of alcohol in combination with varenicline and varenicline alone. Mean (±SEM) alcohol appropriate-responses (A) and response rate (B) following varenicline injection in alcohol discrimination-trained rats. Varenicline did not have alcohol-like discriminative stimulus effects. Mean (±SEM) alcohol-appropriate responses (C) and response rate (D) following varenicline pretreatment prior to the alcohol training dose (1 g/kg). Horizontal dashed line (>80%) represents full expression of the discriminative stimulus effects of alcohol. *- p < 0.05, different from saline treatment.

Figure 3

Effects of varenicline on alcohol self-administration. Mean (±SEM) alcohol responses (A) and alcohol responses across the session (B) following varenicline injection. * - p < 0.05 different from saline treatment.

Figure 4

Effects of alcohol priming on alcohol self-administration. Mean (±SEM) alcohol responses (A) and alcohol responses across the session (B) following alcohol priming doses. * - p < 0.05 different from water treatment.

Figure 5

Effects of alcohol priming combined with varenicline treatment on alcohol self-administration. Mean (±SEM) alcohol responses (A) and alcohol responses across the session (B) following varenicline injection and alcohol priming in rats trained to self-administer alcohol. * - p < 0.05, different from water (A) or saline (B).

Figure 6

Effects of alcohol priming on alcohol seeking behavior. Mean (±SEM) alcohol responses (A) and alcohol responses across the session (B) following alcohol priming and under probe-extinction conditions. * - p < 0.05, different from water pretreatment.

Figure 7

Effects of alcohol priming combined with varenicline on alcohol seeking behavior. Mean (±SEM) alcohol responses (A) and alcohol responses across the session (B) following alcohol priming and varenicline pretreatment, under probe-extinction conditions. * - p < 0.05, different from water pretreatment.