Nicotinic facilitation of delta9-tetrahydrocannabinol discrimination involves endogenous anandamide.
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.
Solinas
Marcello
M
Laboratoire de Biologie et Physiologie Cellulaires, Centre National de la Recherche Scientifique-VMR6187, University of Poitiers, 40 Avenue du Recteur Pineau, 86022, Poitiers, France. marcello.solinas@univ-poitiers.fr
Scherma
Maria
M
Tanda
Gianluigi
G
Wertheim
Carrie E
CE
Fratta
Walter
W
Goldberg
Steven R
SR
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology*; D012054:Reinforcement, Psychology; D012601:Scopolamine / Q000494:pharmacology
D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D010862:Pilocarpine; D008464:Mecamylamine; D009538:Nicotine; D013759:Dronabinol; D012601:Scopolamine; C078814:anandamide