title: Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade.
abstract: We clarified the modulating action of the endocannabinoid system, and its possible mediation by the arachidonic acid cascade, on the reinstatement of methamphetamine (METH)-seeking behavior, using the intravenous self-administration paradigm in rats. Following 12 days of self-administration of METH, the replacement of METH with saline resulted in a gradual decrease in lever press responses (extinction). Under extinction conditions, METH-priming or re-exposure to cues previously paired with METH infusion markedly increased the responses (reinstatement of drug-seeking). The cannabinoid CB1 receptor antagonist, SR141716A, blocked this behavior. Although the cannabinoid agonist, Delta8-tetrahydrocannabinol (THC), had no effects by itself, coadministration of the agonist and METH at small doses reinstated the drug-seeking behavior. THC attenuated the effects of the reinstatement-inducing dose of METH, but enhanced the effect of cues. Either given repeatedly during the extinction or singly, 24 h before the first METH-priming or cues challenge, THC suppressed the reinstatement. In another set of experiments, we found that diclofenac, a cyclooxygenase inhibitor, also attenuated the reinstatement induced by exposure to cues or drug-priming. These results suggest that the endocannabinoid system, through possible mediation by the arachidonic acid cascade, serves as a modulator of the reinstating effects of METH-priming and cues. Extending the current view on the treatment of drug dependence, these results indicate that endocannabinoid-activating substances as well as cyclooxygenase inhibitors may be promising as antirelapse agents.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kusnandar
authors.initials: K
authors.lastname: Anggadiredja
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakamichi
authors.forename: Takato
authors.initials: T
authors.lastname: Hiranita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Shoyama
authors.forename: Shigenori
authors.initials: S
authors.lastname: Watanabe
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D019969:Amphetamine-Related Disorders / Q000523:psychology*; D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology*; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D000697:Central Nervous System Stimulants; D003463:Cues; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D008694:Methamphetamine; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077285:Rimonabant; D055502:Secondary Prevention; D012646:Self Administration
chemical_list: D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D000697:Central Nervous System Stimulants; D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D004008:Diclofenac; D016718:Arachidonic Acid; D008694:Methamphetamine; D013759:Dronabinol; D000077285:Rimonabant