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Functional Interaction between Chronic Nicotinic Acetylcholine Receptor (nAChR) Subtype Agonists and Acute Ethanol‐Induced Cerebellar Ataxia in Mice: Development of Cross‐Tolerance

Well documented functional interaction between nicotine and ethanol may explain their co‐abuse. We have previously reported that attenuation of ethanol ataxia occurs via nAChR subtypes α4 β2 and α7. Now we report possible development of cross‐tolerance between these two psychoactive drugs. CD‐1 male mice weighing 24‐28g were implanted with guide cannulas for chronic intracerebellar (ICB) infusion of drugs. Ataxia was assessed by Rotorod at 15, 30, 45 and 60 min after ethanol (2g/kg;i.p.) challenge. Immunohistochemical study on mice brains was done using α4 and α7 subtype selective antibodies. Chronic ICB infusion of α4 β2‐ and α7‐ selective agonists, RJR‐2403 (31.25, 62.5, 125ng) for 1,3,5,7 days and PNU 282987 (25ng, 250ng, 2.5 μg) for 1, 2, 3, 5 days, respectively, attenuated acute ethanol ataxia dose‐dependently indicating the development of cross‐tolerance between ethanol ataxia and α4 β2 and α7 agonists. Cross‐tolerance was maximal after 5‐day RJR‐2403 treatment and lasted 48 h. However, the cross‐tolerance peaked after 1‐day treatment with PNU 282987 and lasted 72h. Pretreatment with α4 β2‐ and α7‐selective antagonists, DH βE and MLA, abolished the cross‐tolerance indicating nAChR α4 β2 and α7 participation . Immunoreactivity was high for α4 and α7 subtypes in Purkinje cells but sparse in molecular and granular layers. Overall, the results indicate development of cross tolerance between nAChR subtype α4 β2 and α7 selective agonists and ethanol induced ataxia. The observed cross tolerance probably suggests that alcoholics sustain high smoking rate in an attempt to overcome ethnaol's ataxia and other CNS effects thereby contributing to co‐abuse of nicotine and ethanol and subsequent high co‐morbidity associated with these drugs.