title: Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.
abstract: The mechanism through which marijuana produces its psychoactive effects is Δ(9)-tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical "first step" in determination of the role of these endocannabinoids in THC׳s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC׳s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects.
authors.affiliation: RTI International, Research Triangle Park, NC 27709-2194, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. Electronic address: jwiley@rti.org.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: D Matthew
authors.initials: DM
authors.lastname: Walentiny
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: M Jerry
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Beardsley
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Burston
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Poklis
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Vann
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004192:Discrimination, Psychological / Q000187:drug effects*; D013759:Dronabinol / Q000494:pharmacology*; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D013759:Dronabinol; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C094503:glyceryl 2-arachidonate; C078814:anandamide
keywords: 2-Arachidonoylglycerol; Anandamide; JZL184; PF3845; URB597; Δ(9)-tetrahydrocannabinol