The nicotinic acetylcholine receptor partial agonist varenicline increases the ataxic and sedative-hypnotic effects of acute ethanol administration in C57BL/6J mice

Abstract

Background: The costs associated with alcohol abuse are staggering, therefore much effort has been put into developing new pharmacologic strategies to decrease alcohol abuse. Recently, the nicotinic acetylcholine receptor (nAChR) partial agonist varenicline has been shown to decrease ethanol consumption in both humans and animal models.

Methods: We examined the effects of varenicline on the ataxic and sedative-hypnotic effects of ethanol. First, varenicline was administered prior to placement in a locomotor activity chamber to determine whether varenicline influenced baseline locomotor activity. To determine the effect of nicotinic modulation on ethanol-induced motor incoordination, varenicline was administered 30 minutes prior to an acute ethanol injection and then mice were tested on the balance beam, dowel test, or fixed-speed rotarod. To examine ethanol's sedative-hypnotic effects, varenicline was administered 30 minutes prior to 4 g/kg ethanol and the duration of loss of righting reflex (LORR) was measured.

Results: Varenicline markedly reduced baseline locomotor activity in C57BL/6J mice. Varenicline increased ethanol-induced ataxia when measured on the balance beam and dowel test but had no effect when measured on the fixed-speed rotarod. Pretreatment with varenicline increased the duration of LORR.

Conclusions: These data provide evidence that nAChRs may be involved in the ataxic and sedative effects of ethanol. It is possible that one mechanism that could contribute to the ability of varenicline to decrease ethanol consumption may be through increasing negative behavioral effects of alcohol.

Fig. 1

Acute varenicline administration decreases locomotor activity. Data (mean ± SEM) represent locomotor activity of (A) female and (B) male mice following an acute injection of varenicline. N=7-8 per group. *; p < 0.05, significantly different from saline; #; p < 0.05, significantly different from 1 mg/kg varenicline.

Fig. 2

Varenicline increases ethanol-induced motor incoordination as measured on the balance beam. Data (mean ± SEM) represent the number of footslips corrected by the average number of footslips of the corresponding saline group (saline: 0.43 ± 0.25, 0.5 mg/kg: 0.5 ± 0.17; 1 mg/kg: 0.21 ± 0.11; 2 mg/kg: 0.21 ± 0.11) . N=14-17 per group. *; p < 0.05.

Fig. 3

Varenicline increased ethanol-induced motor incoordination as measured in the dowel test. Data (mean ± SEM) represent the latency to fall from a 15.9 mm dowel (A) immediately after or (B) 30 min after a 1.5 g/kg ethanol injection. N=15-17 per group. *; p < 0.05.

Fig. 4

Varenicline does not alter ethanol-induced ataxia as measured on the rotarod. Data (mean ± SEM) represent 23-25 mice per group.

Fig. 5

Varenicline increases ethanol-induced sedation as measured by LORR in C57BL/6J mice. Data (mean ± SEM) represent the length of time the mouse was unable to right itself after a 4 g/kg dose of ethanol. N=21 per group. *; p < 0.05.