Solinas Marcello, Scherma Maria, Tanda Gianluigi, Wertheim Carrie E, Fratta Walter, Goldberg Steven R
Laboratoire de Biologie et Physiologie Cellulaires, Centre National de la Recherche Scientifique-VMR6187, University of Poitiers, 40 Avenue du Recteur Pineau, 86022, Poitiers, France.
J Pharmacol Exp Ther. 2007 Jun;321(3):1127-34. doi: 10.1124/jpet.106.116830. Epub 2007 Mar 9.
Systemic administration of the main active ingredient in cannabis, Delta9-tetrahydrocannabinol (THC), alters extracellular levels of acetylcholine in several brain areas, suggesting an involvement of the cholinergic system in the psychotropic effects of cannabis. Here, we investigated whether drugs acting at either nicotinic or muscarinic receptors can modulate the discriminative effects of THC. In rats that had learned to discriminate effects of 3 mg/kg i.p. injections of THC from injections of vehicle, the nicotinic agonist nicotine (0.1-0.56 mg/kg subcutaneous) and the muscarinic agonist pilocarpine (0.3-3 mg/kg i.p.) did not produce THC-like effects, but they both potentiated the discriminative effects of low doses of THC (0.3-1 mg/kg). Neither the nicotinic antagonist mecamylamine (1-5.6 mg/kg i.p.) nor the muscarinic antagonist scopolamine (0.01-0.1 mg/kg i.p.) altered the discriminative effects of THC, but they blocked the potentiation of discriminative effects of THC by nicotine and pilocarpine, respectively. The cannabinoid CB(1) antagonist rimonabant (1 mg/kg i.p.) reversed nicotine- but not pilocarpine-induced potentiation of THC discrimination, suggesting that nicotine potentiation is, at least in part, mediated by release of endogenous cannabinoids in the brain. In addition, when metabolic degradation of the endogenous cannabinoid anandamide was blocked by the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoylbiphenil-3-yl-ester (URB-597; 0.3 mg/kg i.p.) nicotine, but not pilocarpine, produced significant THC-like discriminative effects that were antagonized by rimonabant. Our results suggest that nicotinic and muscarinic cholinergic receptors modulate the discriminative effects of THC by fundamentally different mechanisms. Nicotinic, but not muscarinic, modulation of THC discrimination involves elevations in endogenous levels of anandamide.
大麻中的主要活性成分Δ9-四氢大麻酚（THC）经全身给药后，会改变多个脑区的细胞外乙酰胆碱水平，这表明胆碱能系统参与了大麻的精神作用。在此，我们研究了作用于烟碱受体或毒蕈碱受体的药物是否能调节THC的辨别效应。在已学会区分腹腔注射3mg/kg THC与注射溶剂效应的大鼠中，烟碱激动剂尼古丁（0.1 - 0.56mg/kg皮下注射）和毒蕈碱激动剂毛果芸香碱（0.3 - 3mg/kg腹腔注射）未产生类似THC的效应，但它们均增强了低剂量THC（0.3 - 1mg/kg）的辨别效应。烟碱拮抗剂美加明（1 - 5.6mg/kg腹腔注射）和毒蕈碱拮抗剂东莨菪碱（0.01 - 0.1mg/kg腹腔注射）均未改变THC的辨别效应，但它们分别阻断了尼古丁和毛果芸香碱对THC辨别效应的增强作用。大麻素CB(1)拮抗剂利莫那班（1mg/kg腹腔注射）逆转了尼古丁诱导的而非毛果芸香碱诱导的THC辨别增强作用，这表明尼古丁的增强作用至少部分是由脑内内源性大麻素的释放介导的。此外，当脂肪酸酰胺水解酶抑制剂环己基氨基甲酸3'-氨基甲酰联苯-3-基酯（URB - 597；0.3mg/kg腹腔注射）阻断内源性大麻素花生四烯乙醇胺的代谢降解时，尼古丁而非毛果芸香碱产生了显著的类似THC的辨别效应，且该效应被利莫那班拮抗。我们的结果表明，烟碱和毒蕈碱胆碱能受体通过根本不同的机制调节THC的辨别效应。对THC辨别效应的烟碱调节而非毒蕈碱调节涉及花生四烯乙醇胺内源性水平的升高。
