The Effects of Long-Term Varenicline Administration on Ethanol and Sucrose Seeking and Self-Administration in Male P Rats

Abstract

Background: Varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic cholinergic receptors, is FDA-approved for treatment of smoking cessation and has been found to reduce alcohol craving in clinical populations. In rodents, varenicline decreases free-choice ethanol (EtOH) intake with somewhat mixed findings in operant paradigms that utilize a combined appetitive/consummatory response.

Methods: The present experiment utilized an operant paradigm that procedurally separates appetitive from consummatory responding and a "reward-blocking" approach (i.e., rats were able to consume EtOH during treatment) to better understand the efficacy of varenicline as a treatment for EtOH self-administration and subsequent EtOH seeking. Separate groups of EtOH- and sucrose-reinforced alcohol-preferring, male P rats experienced alternating cycles of vehicle (2-week cycles) and varenicline (0.3, 1.0, and 2.0 mg/kg self-administered in a gelatin preparation) treatment (3-week cycles) prior to daily sessions where a single lever press resulted in 20 minutes of reinforcer access. At the end of each cycle, a single extinction session assessed the seeking response in the absence of drug pretreatment.

Results: Varenicline dose dependently decreased EtOH intake. Sucrose intake was largely unaffected, with no overall treatment effects and only sporadic days where the medium and high dose differed from vehicle. Neither sucrose nor EtOH seeking was significantly decreased by varenicline, and there were no treatment effects on either lick or lever-press latency. Overall effect sizes were much greater for both drinking and seeking in the EtOH group as compared to the sucrose group.

Conclusions: Varenicline effectively attenuates EtOH self-administration during treatment, but the experience with EtOH consumption while varenicline is "on board" is not sufficient to alter subsequent EtOH seeking. The overall pattern of findings indicates that varenicline blocks the rewarding properties of EtOH while not substituting for EtOH, that the nonspecific effects on an alternate reinforcer are negligible, and that blood levels of varenicline need to be maintained in order for treatment to remain effective.

Keywords: Appetitive; Consummatory; Craving.

Fig 1

In the ethanol-reinforced group (n=12), mean (±SEM) ethanol intake (g/kg) over days following either vehicle or varenicline treatment (data from days preceding the dotted line were analyzed by Day and Dose). Inset: Total mean (±SEM) ethanol intake collapsed over all days. One asterisk indicates a main effect of treatment and significant difference relative to vehicle, two indicate a difference relative to both vehicle and the low dose. See text for specific effects of doses on individual days.

Fig 2

In the sucrose-reinforced group (n=9), mean (±SEM) sucrose intake (g/kg) over days following either vehicle or varenicline treatment (data from days preceding the dotted line were analyzed by Day and Dose). Inset: Total mean (±SEM) sucrose intake collapsed over all days. See text for specific effects of doses on individual days.

Fig. 3

Mean (±SEM) lever-press responses during single, nonreinforced extinction sessions in the ethanol and sucrose groups (as indicated) following prior exposure to vehicle or varenicline during reinforced sessions.