Received for publication November 13, 2006.
Revised March 6, 2007.
Accepted for publication March 6, 2007.

Nicotinic facilitation of delta-9-tetrahydrocannabinol (THC) discrimination involves endogenous anandamide

Abstract

Systemic administration of the main active ingredient in cannabis, delta-9-tetrahydrocannabinol (THC), alters extra-cellular 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 intraperitoneal (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 THC's discriminative effects by nicotine and pilocarpine, respectively. The cannabinoid CB₁ 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 (FAAH) inhibitor 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.

Key words: THC, addiction, behavior, endocannabinoid, muscarinic receptors, nicotinic receptors