Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice

Abstract

Adolescence is a critical period in brain development that coincides with the initiation of alcohol use. Nicotinic acetylcholine receptors (nAChR) have been shown to modulate ethanol behaviors in adult humans and in animal models; however, the role of these receptors in adolescent ethanol behaviors has not been explored. Throughout adolescence, nAChR expression undergoes large-scale developmental changes which may alter behavioral responses to ethanol. Here we examined the effect of varenicline, a nAChR partial agonist, on ethanol consumption, ataxia, sedation, and metabolism in adolescent male and female C57BL/6J mice. The effect of varenicline on ethanol consumption was tested through the Drinking-in-the-Dark (DID) paradigm that models binge-like ethanol consumption. To ensure that results were specific for ethanol, we also tested the effect of varenicline on saccharin consumption. Additionally, varenicline was administered 30min prior to an acute injection of ethanol before being tested for ataxia on the balance beam, sedation using the loss of righting reflex, or ethanol metabolism. Varenicline dose dependently decreased ethanol consumption, but also influenced saccharin intake. Varenicline showed no significant effect on ethanol metabolism, ataxia, or sedation. Unlike its effects in adult animals, varenicline is able to reduce ethanol consumption without increasing the ataxic and sedative effects of ethanol. This work suggests that the neurobiological mechanisms of ethanol behaviors may change across the lifespan and highlights the need for more research on the role of nAChRs in ethanol behaviors throughout development.

Keywords: Ataxia; Consumption; Ethanol; Nicotinic acetylcholine receptors; Sedation; Varenicline.

Fig 1. Varenicline decreased binge-like ethanol consumption and saccharin consumption in adolescent male and female C57BL/6J mice

Data (mean ± SEM) represent ethanol consumption (A) and saccharin consumption (B). There was a main effect of sex on saccharin consumption such that females consumed more saccharin that males (F_{1, 22}=9.3, p<0.01; 20.0 ± 2.4, 12.9 ± 2.0, respectively), but this did not interact with treatment, thus the data for both sexes are shown combined. N = 12 animal per dose for saccharin consumption and 24 animals per dose for ethanol consumption. Asterisks, p < 0.05 from the control group.

Fig 2. Varenicline does not modulate ethanol-induced ataxia in adolescent male and female C57BL/6J mice

Data (mean ± SEM) represent corrected footslips (ethanol slips – baseline slips). N = 13 - 17 animals per dose. Asterisks, p < 0.05 between groups.

Fig 3. Varenicline had no effect on the sedative-hypnotic effects of ethanol in adolescent male and female mice

Data (mean ± SEM) represent time to LORR (A) and duration of LORR (B). For duration of LORR, there was a significant main effect of sex such that females were more sensitive to the sedative effects of ethanol compared to males (F_{1, 71}=4.1, p<0.05; 75.1 ± 4.2, 62.6 ± 3.9, respectively), but since this did not interact with varenicline treatment the data presented combined. N = 17 – 19 animals per dose.

Fig 4. Varenicline does not alter ethanol metabolism in adolescent male mice

Data (mean ± SEM) represent blood ethanol concentrations (BEC) in male mice. N = 5 animals per dose.