Effects of the CB1R agonist WIN-55,212-2 and the CB1R antagonists SR-141716 and AM-1387:: Open-field examination in rats

This study examined the open-field (O-F) effects in rats of the cannabinoid I receptor (CB I R) agonist WIN-55,212-2 (WIN; 1 to 5.6 mg/kg) and its interaction with the CB1R antagonist/inverse agonist SR-141716 (1 to 5.6 mg/kg). Additionally, separate studies examined the O-F effects of SR-141716 (1 to 10 mg/kg) and a newly synthesized CB1R selective antagonist/inverse agonist AM-1387 (3 and 10 mg/kg) when these ligands were administered alone. Both antagonists are characterized in vitro by decreased of GTP gamma S binding and increased cAMP accumulation (inverse agonism). WIN dose dependently reduced ambulation (horizontal activity) and rearing (vertical activity); SR-141716 completely (WIN 3 mg/kg) or partially (WIN 5.6 mg/kg) normalized these behaviors. WIN alone resulted in circling and in an increased latency to leave the start area of the O-F, effects blocked by all doses of SR-141716. Both the increased scratching and grooming, associated with SR-141716 administration, were attenuated but not abolished by WIN. SR-141716 alone tended to reduce ambulation (significant at 10 mg/kg) and rearing (non-significant), had no effect on latency, and increased scratching and grooming (both frequency and duration), at doses of 3 mg/kg and up. At the doses examined, AM-1387 had no effect on ambulation, rearing, latency but significantly increased scratching (10 mg/kg); there was also a trend for increased grooming (both frequency and duration). The O-F profile of WIN suggests more similarity with the effects of THC rather than methanandamide (and presumably also anandamide). Intrinsic activity (scratching and grooming) by SR-141716 was re-affirmed and seemed to be associated with administration of AM-1387 as well. AM-1387 was less potent than SR-141716. (c) 2006 Elsevier Inc. All rights reserved.