Antagonism of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rats and rhesus monkeys.

A newly developed cannabinoid antagonist, SR141716A [N-(piperidin-1-yl)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxa mide hydrochloride], binds to brain cannabinoid receptors and has been shown to block characteristic pharmacological effects of the aminoalkylindole cannabinoid agonist, WIN 55,212-2 (R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpho- linyl)methyl]pyrol-(1,2,3-de]-1,4-benzoxazin-6-yl)(1-n aphthalenyl)methanone monomethanesulfonate). In the present study, the effects of this compound in an animal model of cannabis intoxication were investigated. Rats were trained to press one lever after being injected with 3 mg/kg of delta 9-tetrahydrocannabinol (delta 9-THC) and to press a second lever after injection with vehicle. Rhesus monkeys also were trained to discriminate between delta 9-THC and vehicle. Results of tests with various doses of SR141716A in combination with 3 mg/kg of delta 9-THC showed that SR141716A produced reversible, dose-dependent antagonism of the discriminative stimulus properties of delta 9-THC in rats, with recovery within 24 hr. SR141716A also blocked the discriminative stimulus effects of delta 9-THC in monkeys. Furthermore, in rats, 1 mg/kg of SR141716A produced a 12-fold rightward shift in the delta 9-THC dose-effect curve and a 43-fold rightward shift in the WIN 55,212-2 dose-effect curve. When SR141716A was administered alone, it did not substitute for delta 9-THC in rats. The present results suggest that SR141716A blocks the discriminative stimulus effects of delta 9-THC via a receptor-mediated mechanism. This drug is the first reliable antagonist of cannabinoid discrimination and would be predicted to block or reverse cannabis intoxication in humans.