α6β2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption

Abstract

Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system have been implicated in ethanol behaviors. In particular, work in genetically engineered mice has demonstrated that α6-containing nAChRs are involved in ethanol consumption and sedation. A limitation of these studies is that the alteration in the receptor was present throughout development. The recently described α6β2 antagonist, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), now makes it possible to test for the involvement of these receptors using a pharmacological approach. The aim of this study was to examine the role of α6β2 nAChRs in ethanol behaviors using a pharmacological approach. Adolescent C57BL/6J mice were treated with bPiDI 30 min prior to testing the mice for binge-like ethanol consumption in the drinking-in-the-dark (DID) test, ethanol-induced motor incoordination using the balance beam, and ethanol-induced sedation using the Loss of Righting Reflex (LORR) paradigm. Adolescent animals were chosen because they express a high amount of α6 mRNA relative to adult animals. Control studies were also performed to determine the effect of bPiDI on locomotor activity and ethanol metabolism. Female mice treated with 20 mg/kg bPiDI had reduced locomotor activity compared to saline-treated animals during the first 30 min following an acute injection. Pretreatment with the α6β2 antagonist reduced adolescent ethanol consumption but also reduced saccharin consumption. No significant effects were observed on ethanol-induced ataxia, sedation, or metabolism. This study provides evidence that α6β2 nAChRs are involved in locomotor activity as well as ethanol and saccharin consumption in adolescent animals.

Keywords: Ataxia; CHRNA6; Consumption; Ethanol; Nicotinic acetylcholine receptors; Sedation.

Fig 1. bPiDI decreases locomotor activity

Data (mean ± SEM) represent line crosses in female (A) and male (B) mice. N = 4 – 5 animals per group. Asterisks, significantly different from the control group.

Fig 2. bPiDI decreased binge-like ethanol consumption and saccharin consumption

Data (mean ± SEM) represent ethanol consumption (A) and saccharin consumption (B). No significant main effects or interactions with sex were observed, so male and female data are combined. N = 24 animals per dose. Asterisks, p < 0.05.

Fig 3. bPiDI does not modulate ethanol-induced ataxia

Data (mean ± SEM) represent corrected footslips (ethanol slips – baseline slips). No significant main effects or interactions with sex were observed, so male and female data are combined. N = 12 – 13 animals per dose.

Fig 4. bPiDI had no effect on ethanol’s sedative-hypnotic effects as measured by LORR

Data (mean ± SEM) represent time to LORR (A) and duration of LORR (B). No significant main effects or interactions with sex were observed, so male and female data are combined. N = 18 – 22 animals per dose.

Fig 5. bPiDI has no effect on metabolism of an acute injection of ethanol (4 g/kg)

Data (mean ± SEM) represent blood ethanol concentrations (BEC) in female (A) and male (B) mice. N = 9 – 10 animals per dose.