ANTAGONISM OF THE DISCRIMINATIVE STIMULUS EFFECTS OF DELTA-9-TETRAHYDROCANNABINOL IN RATS AND RHESUS-MONKEYS

A newly developed cannabinoid antagonist, SR141716A (4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide hydrochlorid e], binds to brain cannabinoid receptors and has been shown to block c haracteristic pharmacological effects of the aminoalkylindole cannabin oid agonist, WIN 55,212-2 -de)-1,4-benzoxazin-6-yl)(1-naphthalenyl)met hanone monomethanesulfonate). In the present study, the effects of thi s compound in an animal model of cannabis intoxication were investigat ed. Rats were trained to press one lever after being injected with 3 m g/kg of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and to press a se cond lever after injection with vehicle. Rhesus monkeys also were trai ned 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 antag onism of the discriminative stimulus properties of Delta(9)-THC in rat s, with recovery within 24 hr. SR141716A also blocked the discriminati ve 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 55,21 2-2 dose-effect curve. When SR141716A was administered alone, it did n ot substitute for Delta(9)-THC in rats. The present results suggest th at SR141716A blocks the discriminative stimulus effects of Delta(9)-TH C via a receptor-mediated mechanism. This drug is the first reliable a ntagonist of cannabinoid discrimination and would be predicted to bloc k or reverse cannabis intoxication in humans.