Attenuation of ethanol-induced ataxia by α 4β 2 nicotinic acetylcholine receptor subtype in mouse cerebellum: A functional interaction

Abstract

Many epidemiological studies support the notion that people who drink alcohol also smoke cigarettes and vice versa thereby suggesting a possible functional interaction between these two most widely used psychoactive substances. We have earlier demonstrated that direct intracerebellar (ICB) microinfusion of nicotine dose-dependently antagonizes ethanol-induced ataxia and further that this antagonism occurs in a glutamate-nitric oxide-cyclic guanylyl monophosphate (cGMP) sensitive manner. The present study was designed to determine the possible involvement of specific nicotinic acetylcholine receptor (nAChR) subtype α 4β 2 in nicotine-induced attenuation of ethanol ataxia. Using the Rotorod test and direct ICB microinfusion technique in stereotaxically cannulated CD-1 male mice, we performed the Rotorod test following ICB administration of the α 4β 2-selective agonist, (E)- N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403; 31.25, 62.5, 125 ng) on ethanol (2 g/kg; i.p.) ataxia at 15, 30, 45, 60 min post-ethanol injection. RJR-2403 dose-dependently attenuated ethanol ataxia suggesting a role of α 4β 2 subtype in ameliorating ethanol-induced ataxia. Pretreatment with ICB dihydro-β-erythroidine (DHβE: 125, 250, 500, 750 ng), a potent α 4β 2-selective antagonist, significantly reduced RJR-2403's effect further supporting the α 4β 2 involvement. DHβE (ICB) also antagonized ICB nicotine-induced attenuation of ethanol ataxia again reinforcing the role of α 4β 2 subtype. Additional evidence for the role of α 4β 2 subtype was provided when ICB α 4β 2 antisense oligodeoxynucleotide treatment markedly antagonized RJR 2403–induced attenuation of ethanol ataxia compared with missense-treated animals. This was confirmed with an associated decrease in the expression of α 4β 2 subtypes indicated by immunoblot experiments. In conclusion, the results of the present investigation support an important role of α 4β 2 nAChR subtype in the expression of nicotine-induced attenuation of ethanol ataxia.