Varenicline attenuates cue-induced relapse to alcohol, but not nicotine seeking, while reducing inhibitory response control

Abstract

Rationale: Treatment of the most widely abused drugs, nicotine and alcohol, is hampered by high rates of relapse. Varenicline tartrate, an α4β2 nicotinic receptor partial agonist, is currently prescribed as a smoking cessation aid. However, there is emerging evidence that it may also modulate alcohol seeking and cognitive functioning in rats.

Objectives: As preclinical data on alcohol taking and relapse are limited, we used a self-administration-reinstatement model to evaluate the effects of varenicline on operant responding for alcohol (12%, v/v), intravenous nicotine (40 μg/kg/inf.), sucrose (10%, w/v) and on cue-induced relapse to alcohol and nicotine seeking in rats. At the cognitive level, we assed varenicline's effects on 5-choice serial reaction time task (5-CSRTT) performance with a focus on correct responses (attention) and premature responding (impulsivity), modalities that have previously been associated with addictive behaviour.

Results: Varenicline, at doses of 1.5 and 2.5 mg/kg, reduced alcohol and nicotine self-administration and enhanced operant responding for sucrose. At these doses, varenicline reduced cue-induced relapse to alcohol, but not nicotine seeking. In contrast, at 0.5 mg/kg, varenicline facilitated cue-induced nicotine seeking. Similar to nicotine, varenicline increased premature responding at low doses, but had no effect on any of the other behavioural parameters in the 5-CSRTT.

Conclusions: Our data indicate that varenicline specifically reduced responding for nicotine and alcohol, but not for natural reinforcers such as sucrose. Interestingly, varenicline strongly attenuated cue-induced relapse to alcohol seeking, but not nicotine seeking. Varenicline may therefore be a promising aid in the treatment of alcohol addiction.

Fig. 1

Effects of varenicline on self-administration of a nicotine, b alcohol and c sucrose (inactive responses sucrose self-administration (mean ± SEM): 0.0 g/kg, 3 ± 1.6; 0.5 g/kg, 1.7 ± 0.5; 1.5 g/kg, 0.1 ± 0.1; 2.5 g/kg, 0.1 ± 0.1). *p < 0.05 significant difference with respect to 0.0 g/kg group

Fig. 2

Effects of varenicline on cue-induced reinstatement of a nicotine and b alcohol seeking. *p < 0.05 significant difference with respect to 0.0 g/kg group

Fig. 3

Effects of varenicline on 5-choice serial reaction time performance. The following behavioural measures are presented: a percentage correct responses (attention), b number of premature responses (impulsivity), c number of omissions and d latency of correct responses. *p < 0.05 significant difference with respect to 0.0 g/kg group

Fig. 4

Effects of varenicline (1.5 mg/kg) on 5-choice serial reaction time performance under increased attentional load by reduced stimulus duration. The following behavioural measures are presented: a percentage correct responses (attention), b number of premature responses (impulsivity), c number of omissions and d latency of correct responses. *p < 0.05 significant difference with respect to 0.0 g/kg group. #p < 0.05 significant difference with respect to stimulus duration 1.0 s