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NEUROPHARMACOLOGY

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

Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina

We have previously demonstrated that acute intracerebellar nicotine or N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), a selective ₄₂ nicotinic acetylcholine receptor (nAChR) agonist, dose dependently attenuates ⁹-tetrahydrocannabinol (⁹THC)-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 ⁹-THC-induced ataxia dose dependently, suggesting the development of cross-tolerance between nicotine or RJR-2403 with 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 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 µg) or dihydro--erythroidine hydrobromide (₄₂ 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 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 ⁹-THC treatment. The "nicotine or RJR-2403 + ⁹-THC" treatments significantly increased cerebellar NO_x levels compared with treatment with ⁹-THC alone, supporting a functional correlation between cerebellar nitric oxide production and cerebellar ⁹-THC-induced ataxia and suggesting participation of nitric oxide in the observed cross-tolerance between nicotine/RJR-2403 and ⁹-THC.

Address correspondence to: Dr. M. Saeed Dar, Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834. E-mail address: darm{at}ecu.edu