The goals of this study were to examine the relationship between intravenous doses of the cannabinoid CB1 receptor antagonist AM281 (N‐(morpholin‐4‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide) and the degree of occupancy of this receptor, and to relate occupancy to the ability of this compound to antagonize the sedative effects of the cannabinoid receptor agonist WIN 55,212‐2. Occupancy was determined by measuring the ability of intravenous doses of AM281 to inhibit in vivo binding of (131I)AM281 in brain areas, and locomotor activity was assessed by measuring the rate of beam crossings in a photocell apparatus. As previously documented, WIN 55,212‐2 (1 mg/kg, i.v.) significantly reduced locomotor activity at early times after administration. Co‐injection of AM281 (0.3 mg/kg i/v) and WIN 55,212‐2 restored the rate of beam crossings to that seen on injection 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 (131I)AM281 by AM281 was 0.45 mg/kg. These observations confirm earlier indications that AM281 is a CB1 receptor antagonist or inverse agonist and suggest the existence of an endogenous cannabinoid tone that moderates exploratory locomotor activity. Synapse 38:477–482, 2000. © 2000 Wiley‐Liss, Inc.
Synapse – Wiley
Published: Dec 15, 2000
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