Role of mouse cerebellar nicotinic acetylcholine receptor (nAChR) α4β2- and α7 subtypes in the behavioral cross-tolerance between nicotine and ethanol-induced ataxia

We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes alpha(4)beta(2) and alpha(7). In the present study, ethanol (2 g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of alpha(4)beta(2)- and alpha(7)-selective agonists. Localization of alpha(4)beta(7) and alpha(7) nAChRs was confirmed immunohistochemically. Cerebellar NOx (nitrite + nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the alpha(4)beta(2)-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the alpha(7)-selective agonist, PNU-282987 (1, 2, 3 or 5 days), dose-dependently attenuated ethanol-induced ataxia. These results suggest the development of cross-tolerance between ethanol-induced ataxia and alpha(4)beta(2) and alpha(7) nAChR agonists. With RJR-2403, the cross-tolerance was maximal after a 5-day treatment and lasted 48 h. Cross-tolerance was maximal after a 1-day treatment with PNU-282987 and lasted 72 h. Pretreatment with alpha(4)beta(2)- and alpha(7)-selective antagonists, dihydro-beta-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming alpha(4)beta(2) and alpha(7) involvement. Repeated agonist infusions elevated cerebellar NOx 16 h after the last treatment while acute ethanol exposure decreased it. Pretreatment with repeated RJR-2403 or PNU-282987 reversed ethanol-induced decrease in NOx. The NOx data suggests the involvement of the nitric oxide (NO)-cGMP signaling pathway in the cross-tolerance that develops between alpha(4)beta(2)- and alpha(7)-selective agonists and ethanol ataxia. Both alpha(4)beta(2) and alpha(7) subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for alpha(4)beta(2) and alpha(7) nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism. (C) 2010 Elsevier B.V. All rights reserved.