CENTRAL MEDIATION OF THE CANNABINOID CUE - ACTIVITY OF A SELECTIVE CB1 ANTAGONIST, SR 141716A

Active cannabimimetic drugs are known to bind to two receptor subtypes : one, called CB1, Is mainly localised in the central nervous system w hile the other (CB2) is expressed preferentially in the immune system. SR 141716A has been demonstrated to have a nanomolar affinity for CB1 receptor subtypes and a micromolar affinity for CB2 receptors. Moreov er, it is an effective antagonist at these receptors both in vitro (an tagonism of cannabinoid activity in vas deferens) and in vivo (suppres sion of the hypothermia elicited by WIN 55,212-2). The present experim ents were thus undertaken to investigate the role of CBI receptors in cannabinoid discrimination. Rats were trained to discriminate WIN 55,2 12-2 (0.3 mg/kg s.c.) from saline in a standard operant (FR10) food re warded discrimination procedure. Acquisition of the discrimination req uired 16 days on average and the ED(50) Of WIN 55,212-2 was 0.032 mg/k g s.c. CP55,940 and delta-9-tetrahydrocannabinol (Delta(9)-THC) genera lised to the WIN 55,212-2 stimulus with the respective ED(50)s Of 0.00 7 mg/kg (s.c.) and 0.64 mg/kg (p.o.). Pretreatment with SR 141716A ant agonised the cue elicited by WIN 55,212-2 (ED(50) = 1.6 mg/kg) as well as the generalisation to CP 55,940 (ED(50) = 0.08 mg/kg) and to Delta (9)-THC (ED(50) = 0.15 mg/kg). SR 140098 is a CBI antagonist as potent as SR 141716A in vitro. This compound is unlikely to pass into the br ain since it failed to displace [H-3]-CP55,940 from rat brain membrane s ex vivo, and to reverse WIN 55,212-2-induced hypothermia. SR 140098, in contrast to SR 141716A, did not antagonise the WIN 55,212-2 stimul us. Taken together, the present results demonstrate that the brain CBI receptor subtype mediates the cannabinoid cue.