Antagonism of the discriminative stimulus effects of Delta super(9)-tetrahydrocannabinol in rats and rhesus monkeys

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 275; no. 1; pp. 1 - 6
• Main Authors: Wiley, J L, Lowe, JA, Balster, R L, Martin, B R
• Format: Journal Article
• Language: English
• Published: 01.01.1995
• Subjects: Cannabis sativa; Macaca
• ISSN: 0022-3565

A newly developed cannabinoid antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl) 1-(2,4-dichlorophenyl) 4-methyl-1H-pyr azole-3-carboxamide 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-naphthalenyl)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 super(9)-tetrahydrocannabinol ( Delta super(9)-THC) and to press a second lever after injection with vehicle. Rhesus monkeys also were trained to discriminate between Delta super(9)-THC and vehicle. Results of tests with various doses of SR141716A in combination with 3 mg/kg of Delta super(9)-THC showed that SR141716A produced reversible, dose-dependent antagonism of the discriminative stimulus properties of Delta super(9)-THC in rats, with recovery within 24 hr. SR141716A also blocked the discriminative stimulus effects of Delta super(9)-THC in monkeys. Furthermore, in rats, 1 mg/kg of SR141716A produced a 12-fold rightward shift in the Delta super(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 super(9)-THC in rats. The present results suggest that SR141716A blocks the discriminative stimulus effects of Delta super(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.