Behavioral Cross-Tolerance between Repeated Intracerebellar Nicotine and Acute {Delta}9-Tetrahydrocannabinol-Induced Cerebellar Ataxia: Role of Cerebellar Nitric Oxide.

We have previously demonstrated that acute intracerebellar nicotine or N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), a selective alpha(4)beta(2) nicotinic acetylcholine receptor (nAChR) agonist, dose dependently attenuates Delta(9)-tetrahydrocannabinol (Delta(9)THC)-induced ataxia. Presently, we have shown that intracerebellar nicotine (1.25, 2.5, and 5 ng; once daily for 5 days) and RJR-2403 (250, 500, and 750 ng; once daily for 5 days) significantly attenuate cerebellar Delta(9)-THC-induced ataxia dose dependently, suggesting the development of cross-tolerance between nicotine or RJR-2403 with Delta(9)-THC in male CD-1 mice. Intracerebellar RJR-2403 (750 ng) microinfused for 1, 2, 3, 5, and 7 days (once daily) significantly attenuated Delta(9)-THC-induced ataxia in the 3-, 5-, and 7-day treatment groups; optimal cross-tolerance was evident at day 5 and persisted till 36 h after the last RJR-2403 microinfusion. Intracerebellar microinfusion of hexamethonium (nAChR antagonist; 1 mug) or dihydro-beta-erythroidine hydrobromide (alpha(4)beta(2) nAChR antagonist; 500 ng) for 5 days 10 min before daily intracerebellar nicotine or RJR-2403 microinfusion virtually abolished cross-tolerance between nicotine or RJR-2403 and Delta(9)-THC, indicating nAChR participation. In addition, microinfusion of antagonists 10 min after daily intracerebellar nicotine or RJR-2403 failed to alter the cross-tolerance, suggesting possible involvement of downstream cerebellar second-messenger mechanisms. Finally, the cerebellar concentration of nitric oxide products [total sum of nitrite + nitrate (NO(x))] was increased after 5 days of intracerebellar nicotine or RJR-2403 treatment, which was decreased by acute intracerebellar Delta(9)-THC treatment. The "nicotine or RJR-2403 + Delta(9)-THC" treatments significantly increased cerebellar NO(x) levels compared with treatment with Delta(9)-THC alone, supporting a functional correlation between cerebellar nitric oxide production and cerebellar Delta(9)-THC-induced ataxia and suggesting participation of nitric oxide in the observed cross-tolerance between nicotine/RJR-2403 and Delta(9)-THC.