Activation of brain prostanoid EP3 receptors via arachidonic acid cascade during behavioral suppression induced by Delta8-tetrahydrocannabinol.
We have previously shown that behavioral changes induced by cannabinoid were due to an elevation of prostaglandin E2 (PGE2) via the arachidonic acid cascade in the brain. In the present study, we investigated the participation of the prostanoid EP3 receptor, the target of PGE2 in the brain, in behavioral suppression induced by Delta8-tetrahydrocannabinol (Delta8-THC), an isomer of the naturally occurring Delta9-THC, using a one-lever operant task in rats. Intraperitoneal administration of Delta8-THC inhibited the lever-pressing behavior, which was significantly antagonized by both the selective cannabinoid CB1 receptor antagonist SR141716A and the cyclooxygenase inhibitor diclofenac. Furthermore, intracerebroventricular (i.c.v.) administration of PGE2 significantly inhibited the lever-pressing performance similar to Delta8-THC. Prostanoid EP3 receptor antisense-oligodeoxynucleotide (AS-ODN; twice a day for 3 days, i.c.v.) significantly decreased prostanoid EP3 receptor mRNA levels as determined by the RT-PCR analysis in the cerebral cortex, hippocampus and midbrain. AS-ODN also antagonized the PGE2-induced suppression of the lever pressing. In the same way, the suppression of lever-pressing behavior by Delta8-THC was significantly improved by AS-ODN. It is concluded that the suppression of lever-pressing behavior by cannabinoid is due to activation of the prostanoid EP3 receptor through an elevation of PGE2 in the brain.
Yamaguchi
Taku
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Kubota
Takashi
T
Watanabe
Shigenori
S
Yamamoto
Tsuneyuki
T
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D011453:Prostaglandins; C545649:Ptger3 protein, rat; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016718:Arachidonic Acid; C035731:delta-8-tetrahydrocannabinol; D013759:Dronabinol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat