title: Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281.
abstract: 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 [(131)I]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 IC(50) value for displacement of [(131)I]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.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cosenza
authors.forename: A N
authors.initials: AN
authors.lastname: Gifford
authors.forename: S J
authors.initials: SJ
authors.lastname: Gatley
authors.forename: B
authors.initials: B
authors.lastname: Pyatt
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
mesh_terms: D000818:Animals; D048588:Benzoxazines; D001921:Brain / Q000378:metabolism*; D004338:Drug Combinations; D008297:Male; D051379:Mice; D009025:Morpholines / Q000378:metabolism* / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology; D011720:Pyrazoles / Q000378:metabolism*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048588:Benzoxazines; D004338:Drug Combinations; D009025:Morpholines; D009281:Naphthalenes; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C109925:AM 281