title: Possible role of mouse cerebellar nitric oxide in the behavioral interaction between chronic intracerebellar nicotine and acute ethanol administration: observation of cross-tolerance.
abstract: Many studies have reported cross-tolerance between nicotine and ethanol. Previously we demonstrated that intracerebellar nicotine attenuates ethanol-induced motor impairment. In this study, intracerebellar nicotine (0.625, 2.5, 5 ng; once daily for five days) significantly attenuated ethanol-induced motor impairment in a dose-dependent fashion suggesting the development of cross-tolerance between nicotine and ethanol in male CD-1 mice. Using the same paradigm, intracerebellar nicotine (5 ng) microinfused for 1, 2, 3, 5, 7 days significantly attenuated ethanol-induced motor impairment in all groups except the 1-day treatment group. Cross-tolerance, which developed optimally in 5-day nicotine treatment group, was reversible and detectable up to 40 h post-nicotine microinfusion. Intracerebellar microinfusion of hexamethonium (1 mug once daily for 5 days): (i) did not alter ethanol-induced motor impairment indicating no tonic nicotine receptor involvement; (ii) 10 min prior to daily intracerebellar nicotine treatment virtually abolished the cross-tolerance between nicotine and ethanol indicating nicotinic acetylcholine receptor participation; (iii) when microinfused 10 min after daily intracerebellar nicotine treatment, failed to abolish the cross-tolerance which suggested possible participation of downstream second messenger mechanisms. Chronic intracerebellar microinfusion of nicotine: (i) failed to attenuate acute pentobarbital (25mg/kg i.p.)-induced motor impairment; and (ii) produced no change in normal motor coordination when followed by saline injection. Finally, the cerebellar concentration of total nitric oxide products (nitrite+nitrate; NO(x)); (i) was increased after 5-day intracerebellar nicotine; (ii) was decreased by acute ethanol administration; and (iii) decreased due to acute ethanol administration which was opposed by chronic intracerebellar nicotine treatment. These results support a functional correlation between the cerebellar nitric oxide production and ethanol-induced motor impairment and suggest possible participation of nitric oxide as a factor in the observed cross-tolerance between nicotine and ethanol.
authors.affiliation: Department of Pharmacology and Toxicology, Moye Boulevard, Brody School of Medicine, East Carolina University, Brody Building, Room 6S20, Greenville, NC 27834, USA.
authors.forename: S
authors.initials: S
authors.lastname: Al-Rejaie
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Dar
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology*; D004361:Drug Tolerance; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D018738:Hexamethonium / Q000008:administration & dosage / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D010424:Pentobarbital / Q000494:pharmacology; D013238:Stereotaxic Techniques
chemical_list: D009569:Nitric Oxide; D018738:Hexamethonium; D000431:Ethanol; D009538:Nicotine; D010424:Pentobarbital