Locomotor activity and occupancy of brain cannabinoid CB1 receptors by theantagonist/inverse agonist AM281

The goals of this study were to examine the relationship between intravenou s doses of the cannabinoid CB1 receptor antagonist AM281 (N-(morpholin-4-yl )-5-(4-iodophenyl)- 1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxami de) and the degree of occupancy of this receptor, and to relate occupancy t o the ability of this compound to antagonize the sedative effects of the ca nnabinoid receptor agonist WIN 55,212-2. Occupancy was determined by measur ing the ability of intravenous doses of AM281 to inhibit in vivo binding of [I-131]AM281 in brain areas, and locomotor activity was assessed by measur ing the rate of beam crossings in a photocell apparatus. As previously docu mented, WIN 55,212-2 (1 mg/kg, i.v.) significantly reduced locomotor activi ty at early times after administration. Go-injection of AM281 (0.3 mg/kg i/ v) and WIN 55,212-2 restored the rate of beam crossings to that seen on inj ection of vehicle. In addition, AM281 (0.3 mg/kg i/v) approximately doubled locomotor activity between 60-120 min when injected alone. The IC50 value for displacement of [I-131]AM281 by AM281 was 0.45 mg/kg. These observation s confirm earlier indications that AM281 is a CB1 receptor antagonist or in verse agonist and suggest the existence of an endogenous cannabinoid tone t hat moderates exploratory locomotor activity. (C) 2000 Wiley-Liss, Inc.