Behavioral suppression induced by cannabinoids is due to activation of the arachidonic acid cascade in rats.
Tetrahydrocannabinol (THC) is the principle psychoactive ingredient of marijuana and produces various psychoactive effects through the brain cannabinoid (CB1) receptor. The CB1 receptor belongs to the seven-transmembrane domain family of G-protein-coupled receptors and is involved in the arachidonic acid cascade in the brain. Few reports have attempted to clarify the functional role of endogenous cannabinoid and the arachidonic acid cascade through the CB1 receptor using a behavioral paradigm. Therefore, in this study, we clarified the mechanism of cannabinoid-induced suppression of lever pressing in rats, focusing on the arachidonic acid cascade as a novel second messenger of CB1 receptor. Delta(8)-THC and the potent synthetic CB1 receptor agonist HU-210 dose-dependently inhibited lever-pressing performance. The Delta(8)-THC-induced suppression was significantly antagonized by the cyclooxygenase (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 microg/rat, i.c.v.), the final product of the arachidonic acid cascade, significantly inhibited lever pressing similar to Delta(8)-THC and HU-210. In conclusion, we found that suppression of lever-pressing behavior induced by cannabinoids was mediated through activation of the arachidonic acid cascade via the CB1 receptor. Therefore, it is possible that the psychoactive effects of cannabinoid are due to an increase in the formation of PGE(2) in the brain.
Yamaguchi
T
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 812-8582, Fukuoka, Japan.
Shoyama
Y
Y
Watanabe
S
S
Yamamoto
T
T
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects; D015290:Second Messenger Systems / Q000187:drug effects
D002186:Cannabinoids; D016861:Cyclooxygenase Inhibitors; D006213:Hallucinogens; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D004008:Diclofenac; D016718:Arachidonic Acid; D013759:Dronabinol; D015232:Dinoprostone; C062018:HU 211