Attenuation of ethanol-induced ataxia by α4β2 nicotinic acetylcholine receptor subtype in mouse cerebellum: A functional interaction

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 α4β2 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 α4β2-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 α4β2 subtype in ameliorating ethanol-induced ataxia. Pretreatment with ICB dihydro-β-erythroidine (DHβE: 125, 250, 500, 750 ng), a potent α4β2-selective antagonist, significantly reduced RJR-2403's effect further supporting the α4β2 involvement. DHβE (ICB) also antagonized ICB nicotine-induced attenuation of ethanol ataxia again reinforcing the role of α4β2 subtype. Additional evidence for the role of α4β2 subtype was provided when ICB α4β2 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 α4β2 subtypes indicated by immunoblot experiments. In conclusion, the results of the present investigation support an important role of α4β2 nAChR subtype in the expression of nicotine-induced attenuation of ethanol ataxia.