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

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• 作者：Najla Taslim^a ; Ken Soderstrom^a ; M. Saeed Dar ; ^a ; ^darm@ecu.edu
• 关键词：Nicotinic &#x3b1 ; ₄β ; ₂/&#x3b1 ; ₇ subtypes ; Intracerebellar microinfusion ; Ataxia ; Ethanol ; Functional interaction ; Rotorod
• 刊名：Behavioural Brain Research
• 出版年：2011
• 出版时间：1 March 2011
• 年：2011
• 卷：217
• 期：2
• 页码：282-292
• 全文大小：1272 K

文摘

We have demonstrated that nicotine attenuated ethanol-induced ataxia via nicotinic-acetylcholine-receptor (nAChR) subtypes α₄β₂ and α₇. In the present study, ethanol (2 g/kg; i.p.)-induced ataxia was assessed by Rotorod performance following repeated intracerebellar infusion of α₄β₂- and α₇-selective agonists. Localization of α₄β₂ and α₇ nAChRs was confirmed immunohistochemically. Cerebellar NO_x (nitrite + nitrate) was determined flurometrically. Repeated intracerebellar microinfusion of the α₄β₂-selective agonist, RJR-2403 (for 1, 2, 3, 5 or 7 days) or the α₇-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 α₄β₂ and α₇ 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 α₄β₂- and α₇-selective antagonists, dihydro-β-erythroidine and methyllycaconitine, respectively, prevented the development of cross-tolerance confirming α₄β₂ and α₇ involvement. Repeated agonist infusions elevated cerebellar NO_x 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 NO_x data suggests the involvement of the nitric oxide (NO)–cGMP signaling pathway in the cross-tolerance that develops between α₄β₂- and α₇-selective agonists and ethanol ataxia. Both α₄β₂ and α₇ subtypes exhibited high immunoreactivity in Purkinje but sparse expression in molecular and granular cell layers. Our results support a role for α₄β₂ and α₇ nAChR subtypes in the development of cross-tolerance between nicotine and ethanol with the NO signaling pathway as a potential mechanism.