Behavioral suppression induced by cannabinoids is due to activation of thearachidonic acid cascade in rats

Tetrahydrocannabinol (THC) is the principle psychoactive ingredient of mari juana and produces various psychoactive effects through the brain cannabino id (CB1) receptor. The CB1 receptor belongs to the seven-transmembrane doma in family of G-protein-coupled receptors and is involved in the arachidonic acid cascade in the brain. Few reports have attempted to clarify the funct ional role of endogenous cannabinoid and the arachidonic acid cascade throu gh the CB1 receptor using a behavioral paradigm. Therefore, in this study, we clarified the mechanism of cannabinoid-induced suppression of lever pres sing in rats, focusing on the arachidonic acid cascade as a novel second me ssenger of CB1 receptor. Delta (8)-THC and the potent synthetic CB1 recepto r agonist HU-210 dose-dependently inhibited lever-pressing performance. The Delta (8)-THC-induced suppression was significantly antagonized by the cyc looxygenase (COX) inhibitors diclofenac (32 mg/kg, i.p.), aspirin (10 mg/kg , i.p.) and indomethacin (10 mg/kg, i.p.). The suppressive effect of HU-210 was also significantly antagonized by 32 mg/kg diclofenac. Prostaglandin E -2 (3.2 mug/rat, i.c.v.), the final product of the arachidonic acid cascade , significantly inhibited lever pressing similar to Delta (8)-THC and HU-21 0. In conclusion, we found that suppression of lever-pressing behavior indu ced by cannabinoids was mediated through activation of the arachidonic acid cascade via the CB1 receptor. Therefore, it is possible that the psychoact ive effects: of cannabinoid are due to an increase in the formation of PGE( 2) in the brain. (C) 2001 Elsevier Science B.V. All rights reserved.