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 CB1 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 shakes, 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 courses, 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 minutes after SR141716A injection, cAMP accumulation in the cortex, striatum, hippocampus, mesencephalon, and cerebellum was the same as in controls, whereas protein kinase A (PKA) activity was significantly increased in the hippocampus (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 the striatum and hippocampus, suggesting that the change in cAMP level is the earliest event in the G protein-coupled receptor transduction pathway ending in a pharmacological effect after 30 min. When the same assays were done in tolerant animals, no change was seen in either cAMP levels or PKA activity in the brain areas considered. To conclude, we found in vivo that SR141716A acts through activation of the cAMP cascade and our results represent an important point for developing potential therapeutic application for SR141716A.