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 alpha(4)beta(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 alpha(4)beta(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 alpha(4)beta(2) subtype in ameliorating
ethanol-induced
ataxia. Pretreatment with ICB
dihydro-beta-erythroidine (DHbetaE: 125, 250, 500, 750 ng), a potent alpha(4)beta(2)-selective antagonist, significantly reduced RJR-2403's effect further supporting the alpha(4)beta(2) involvement. DHbetaE (ICB) also antagonized ICB
nicotine-induced attenuation of
ethanol ataxia again reinforcing the role of alpha(4)beta(2) subtype. Additional evidence for the role of alpha(4)beta(2) subtype was provided when ICB alpha(4)beta(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 alpha(4)beta(2) subtypes indicated by immunoblot experiments. In conclusion, the results of the present investigation support an important role of alpha(4)beta(2) nAChR subtype in the expression of
nicotine-induced attenuation of
ethanol ataxia.