Nicotine‐Ethanol Interaction: Regulation by two distinct nicotinic acetylcholine receptor (nAChR) subtypes in mouse cerebellum

Abstract

We previously reported cross tolerance between nicotine and ethanol and attenuation of ethanol ataxia by intracerebellar (ICB) nicotine. Using rotorod and direct ICB infusion in cannulated mice, we studied the role of nAChR subtypes á4â2 and á7. RJR‐2403 [32.25, 62.5, 125 ng] a á4â2 agonist, markedly attenuated ethanol (2g/kg; i.p) ataxia dose dependently. Dihydro‐â‐erythroidine, DHâE, á4â2 antagonist, (500ng) significantly attenuated RJR's and nicotine‐induced attenuation of ethanol ataxia reinforcing the role of á4â2 subtype in nicotine‐ethanol functional interaction. Also, ICB infusion of PNU 282987 (250ng–2.5ug), a novel á7 subtype selective agonist reduced ethanol ataxia thus indicating the probable role of á7 nAChR subtype in this context. Moreover, pretreatment with methyllylcaconitine (MLA; 3–12ng; ICB), a á7‐subtype selective antagonist, effectively prevented PNU and nicotine attenuation of ethanol ataxia confirming the contribution of á7 subtype in ethanol's ataxia. Both DHâE and MLA per se had no effect on ethanol's ataxia precluding any tonic role of nAChR subtypes. Taken together, our results support a comparable role of nAChR á4â2 and á7 subtype in nicotine‐induced attenuation of ethanol ataxia. Future treatment strategies for ethanol ataxia might require manipulation of these nAChR subtypes to lessen alcohol related motor impairment.