Modulation of ethanol consumption by genetic and pharmacological manipulation of nicotinic acetylcholine receptors in mice

Abstract

Rationale: Alcohol and nicotine are commonly co-abused. Genetic correlations between responses to these drugs have been reported, providing evidence that common genes underlie the response to alcohol and nicotine. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system are important in mediating nicotine response, and several studies suggest that alcohol may also interact with these nAChRs.

Objective: The aim of this study was to examine the role of nAChRs containing α7 or β2 subunits in ethanol consumption.

Methods: A two-bottle choice paradigm was used to determine ethanol consumption in wild-type and nAChR subunit knockout mice. Challenge studies were performed using the α4β2 nAChR partial agonist varenicline.

Results: Mice lacking the β2 subunit consumed a similar amount of ethanol compared to their wild-type siblings in an ethanol-drinking paradigm. In contrast, mice lacking the α7 nAChR receptor subunit consumed significantly less ethanol than wild-type mice but consumed comparable amounts of water, saccharin, and quinine. In C57BL/6J mice, varenicline dose-dependently decreased ethanol consumption with a significant effect of 2 mg/kg, without affecting water or saccharin consumption. This effect of varenicline was not reversed in mice lacking either the α7 or β2 subunit, providing evidence that nAChRs containing one of these subunits are not required for this effect of varenicline.

Conclusions: This study provides evidence that α7 nAChRs are involved in ethanol consumption and supports the idea that pharmacological manipulation of nAChRs reduces ethanol intake. Additional nAChRs may also be involved in ethanol intake, and there may be functional redundancy in the nicotinic control of alcohol drinking.

Fig. 1

Deletion of the β2 subunit does not alter ethanol consumption. a Ethanol consumption, b saccharin consumption, and c quinine consumption in female β2WT (Chrnb2 WT), β2HET (Chrnb2 HET), and β2KO (Chrnb2 KO) mice. d Ethanol consumption, e saccharin consumption, and f quinine consumption in male β2WT, β2HET, and β2KO mice. Data are represented as mean ± SEM. N=6–10 per group

Fig. 2

Deletion of the α7 subunit of the nAChR significantly decreases ethanol consumption. a Ethanol consumption, b saccharin consumption, and c quinine consumption in female α7WT (Chrna7 WT), α7HET (Chrna7 HET), and α7KO (Chrna7 KO) mice. d Ethanol consumption, e saccharin consumption, and f quinine consumption in male α7WT, α7HET, and α7KO mice. Data are represented as mean ± SEM. N=6–9 per group. *p<0.05

Fig. 3

Pretreatment with varenicline decreases ethanol consumption, but not saccharin consumption in C57BL/6J mice. The effect of pretreatment with varenicline on a ethanol consumption and b saccharin consumption. Data are represented as mean ± SEM for consumption during the first 3 h of choice administration. N=20 per group. *p<0.05

Fig. 4

Pretreatment with varenicline decreases ethanol consumption in β2WT (Chrnb2 WT) and β2KO (Chrnb2 KO) mice. The effect of pretreatment with varenicline on a ethanol consumption and b saccharin consumption. Data are represented as mean ± SEM for consumption during the first 3 h of choice administration. N=13–14 per group. *p<0.05; ^#p=0.05

Fig. 5

Pretreatment with varenicline decreases ethanol consumption in α7WT (Chrna7 WT) and α7KO (Chrna7 KO) mice. The effect of pretreatment with varenicline on a ethanol consumption and b saccharin consumption. Data are represented as mean ± SEM for consumption during the first 3 h of choice administration. N=9 per group. *p<0.05

Fig. 6

Pretreatment with varenicline does not alter ethanol metabolism in C57BL/6J mice. Data (mean ± SEM) represent blood ethanol concentration taken following a 4 g/kg ethanol injection. N=9 per group