Smith Aaron D, Dar M Saeed
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Brain Res. 2006 Oct 18;1115(1):16-25. doi: 10.1016/j.brainres.2006.07.075. Epub 2006 Aug 24.
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.
尽管尼古丁和大麻素在人体内广泛共存，但很少有关于尼古丁和大麻素联合给药的研究报道。此前，我们曾报道小脑内注射（ICB）Δ⁹-四氢大麻酚（Δ⁹-THC）会产生剂量依赖性的小脑共济失调。本研究调查了在CD-1雄性小鼠中，小脑内注射尼古丁对小脑内注射Δ⁹-THC所致共济失调的功能影响。尼古丁（0.625、1.25、2.5、5 ng；ICB）剂量依赖性地显著减轻了Δ⁹-THC引起的共济失调，而小脑内注射六甲铵（5 μg）可消除这种作用，这表明尼古丁的减轻作用是通过烟碱型乙酰胆碱受体（nAChR）介导的。为了进一步研究涉及哪种特定的nAChR亚型，小脑内注射RJR-2403（250、375、500、750 ng），一种α⁴β²选择性nAChR激动剂，显著减轻了Δ⁹-THC引起的共济失调。α⁴β²选择性nAChR拮抗剂DHbetaE（500 ng）几乎完全消除了RJR-2403诱导的Δ⁹-THC共济失调的减轻作用。小脑内注射α⁷选择性nAChR拮抗剂MLA（1、5 μg）未能拮抗尼古丁或RJR-2403诱导的Δ⁹-THC共济失调的减轻作用。这表明α⁷亚型不起作用，并进一步强化了α⁴β²的重要性。此外，小脑内注射DHbetaE几乎完全消除了尼古丁诱导的Δ⁹-THC共济失调的减轻作用，这表明α⁴β²是小脑主要的nAChR亚型。小脑内注射DHbetaE或MLA单独对Δ⁹-THC共济失调无影响，排除了α⁴β²亚型的紧张性作用。因此，本研究结果有力地支持了小脑α⁴β²而非α⁷烟碱受体亚型参与了尼古丁和RJR-2403介导的对Δ⁹-THC共济失调的减轻作用。
