The Role of Nicotinic Acetylcholine Receptor (nAChR) a7Subtype in the Functional Interaction Between Nicotineand Ethanol in Mouse Cerebellum

摘要

Background: Many epidemiological studies report that alcoholics overwhelmingly smoke tobacco and vice versa, which suggests a possible functional interaction between ethanol and nicotine. Although nicotine-ethanol interaction is well documented within the central nervous system, the mechanism is not well understood. Therefore, it is important from a public health standpoint to understand the mechanisms involved in nicotine and ethanol functional interaction. The intrac-erebellar (ICB) administration of nicotine significantly attenuates ethanol ataxia through nicotinic acetylcholine receptor (nAChR) alpha_4beta_2 subtype. This study, an extension of earlier work, was intended to investigate the possible role of nAChR subtype alpha_7 in mitigating ethanol ataxia.Methods: The effect of ICB injection of PNU-282987 (alpha_7 agonist; 25 ng to 2.5 ng) and the antagonist methyllycaconitine was evaluated on ethanol (2 g/kg; i.p.)-induced ataxia with a Roto-rod. Cerebellar nitric oxide was determined fluorometrically in the presence of ethanol and/or PNU-282987.Results: Attenuation of ethanol-induced ataxia following PNU-282987 microinfusion was dose-dependent suggesting the participation of alpha_7 subtype in nicotine and ethanol interaction. Intracerebellar pretreatment with methyllycaconitine (alph_7-selective antagonist; 6 ng) virtually abolished the attenuating effect of PNU-282987 as well as the effect of nicotine, but not of RJR-2403 (alpha_4beta_2-selective agonist; 125 ng) on ethanol-induced ataxia. Finally, ethanol administration significantly decreased cerebellar NO_X, whereas ICB PNU-282987 significantly increased and/or opposed ethanol-induced decrease in NO_X. These results were functionally in agreement with our Rotorod data.Conclusions: These observations confirmed the following: (i) alpha_7 participation in nicotine-ethanol interaction and (ii) alpha_7 selectivity of methyllycaconitine. Overall, the results demonstrate the role of cerebellar nAChR alpha_7 ...