title: Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis.
abstract: Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, delta9-tetrahydrocannabinol, acts by binding to brain CB1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of delta9-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.
authors.affiliation: Department of Psychiatry, McGill University, Montréal, QC, Canada H1N 3V2.
authors.forename: G
authors.initials: G
authors.lastname: Gobbi
authors.forename: F R
authors.initials: FR
authors.lastname: Bambico
authors.forename: R
authors.initials: R
authors.lastname: Mangieri
authors.forename: M
authors.initials: M
authors.lastname: Bortolato
authors.forename: P
authors.initials: P
authors.lastname: Campolongo
authors.forename: M
authors.initials: M
authors.lastname: Solinas
authors.forename: T
authors.initials: T
authors.lastname: Cassano
authors.forename: M G
authors.initials: MG
authors.lastname: Morgese
authors.forename: G
authors.initials: G
authors.lastname: Debonnel
authors.forename: A
authors.initials: A
authors.lastname: Duranti
authors.forename: A
authors.initials: A
authors.lastname: Tontini
authors.forename: G
authors.initials: G
authors.lastname: Tarzia
authors.forename: M
authors.initials: M
authors.lastname: Mor
authors.forename: V
authors.initials: V
authors.lastname: Trezza
authors.forename: S R
authors.initials: SR
authors.lastname: Goldberg
authors.forename: V
authors.initials: V
authors.lastname: Cuomo
authors.forename: D
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D063386:Cannabinoid Receptor Agonists; D002219:Carbamates / Q000494:pharmacology*; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D051381:Rats; D043882:Receptors, Cannabinoid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D001095:Arachidonic Acids; D001549:Benzamides; D063386:Cannabinoid Receptor Agonists; D002219:Carbamates; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D012701:Serotonin; D013759:Dronabinol; C078814:anandamide; D009638:Norepinephrine