In vivo characterization of the specific cannabinoid receptor antagonist, SR141716A: Behavioral and cellular responses after acute and chronic treatments

To characterize the behavioral and biochemical effects of the cannabinoid C B1 antagonist SR141716A, we injected the compound intraperitoneally (ip) at doses from 0.625 mg/kg to 5 mg/kg in rats. SR141716A per se induced a dose -dependent increase of some behavioral signs such as wet dog and head shake s, forepaw fluttering, grooming, and facial rubbing. When the highest dose of SR141716A (5 mg/kg ip) was injected once a day for four days, tolerance developed to most of the behavioral signs, although with different time cou rses, except for grooming behavior, which was still significantly different from controls after the fourth injection although reduced by 38% from the first. To characterize the biochemical mechanism underlying these effects, we designed a series of biochemical studies on specific cerebral areas from rats treated with the highest dose of SR141716A (5 mg/kg ip). Thirty minut es after SR141716A injection, cAMP accumulation in the cortex, striatum, hi ppocampus, mesencephalon, and cerebellum was the same as in controls, where as protein kinase A (PKA) activity was significantly increased in the hippo campus (65%) and striatum (87%). To explain this difference, we performed a cAMP assay at an early time (10 min) and found a significant increase in t he striatum and hippocampus, suggesting that the change in cAMP level is th e earliest event in the G protein-coupled receptor transduction pathway end ing in a pharmacological effect after 30 min. When the same assays were don e in tolerant animals, no change was seen in either cAMP levels or PKA acti vity in the brain areas considered. To conclude, we found in vivo that SR14 1716A acts through activation of the cAMP cascade and our results represent an important point for developing potential therapeutic application for SR 141716A. Synapse 35:8-14, 2000. (C) 2000 Wiley-Liss, Inc.