Mouse cerebellar nicotinic-cholinergic receptor modulation of Delta9-THC ataxia: role of the alpha4beta2 subtype.Brain Res 2006; 1115(1):16-25BR
In spite of widespread association of nicotine and cannabinoids in humans, very few studies in which nicotine and cannabinoids are co-administered have been reported. Previously, we have reported that intracerebellar (ICB) Delta(9)-tetrahydrocannabinol (Delta(9)-THC) produces dose-dependent cerebellar ataxia. The present study investigated the functional consequences of ICB microinfusion of nicotine on ICB Delta(9)-THC ataxia in CD-1 male mice. Nicotine (0.625, 1.25, 2.5, 5 ng; ICB) markedly attenuated Delta(9)-THC ataxia dose dependently, which was abolished by ICB hexamethonium (5 microg), thus suggesting that the attenuation by nicotine occurred via the nicotinic acetylcholine receptor (nAChR). To further investigate which specific nAChR subtype was involved, ICB microinfusion of RJR-2403 (250, 375, 500, 750 ng), a alpha(4)beta(2) selective nAChR agonist, markedly attenuated Delta(9)-THC ataxia. DHbetaE (500 ng), a alpha(4)beta(2) selective nAChR antagonist, virtually abolished RJR-2403-induced attenuation of Delta(9)-THC ataxia. ICB microinfusion of MLA, a alpha(7) selective nAChR antagonist (1, 5 microg) failed to antagonize nicotine or RJR-2403-induced attenuation of Delta(9)-THC ataxia. This suggested a lack of a role of the alpha(7) subtype and further reinforced the significance of alpha(4)beta(2). Additionally, ICB treatment with DHbetaE virtually abolished nicotine-induced attenuation of Delta(9)-THC ataxia that suggested alpha(4)beta(2) as the primary cerebellar nAChR subtype. Lack of effect of ICB DHbetaE or MLA alone on Delta(9)-THC ataxia ruled out a tonic effect of the alpha(4)beta(2) subtype. The results of the present investigation, therefore, strongly support involvement of the cerebellar alpha(4)beta(2), but not alpha(7), nicotinic receptor subtype in the mediation via nicotine and RJR-2403 on attenuation of Delta(9)-THC ataxia.