title: Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.
abstract: Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana, and other direct cannabinoid receptor (CB1) agonists produce a number of neurobehavioral effects in mammals that range from the beneficial (analgesia) to the untoward (abuse potential). Why, however, this full spectrum of activities is not observed upon pharmacological inhibition or genetic deletion of either fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively, has remained unclear. Here, we describe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. Falling into this latter category was drug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were reversed by a CB1 antagonist. These data indicate that AEA and 2-AG signaling pathways interact to regulate specific behavioral processes in vivo, including those relevant to drug abuse, thus providing a potential mechanistic basis for the distinct pharmacological profiles of direct CB1 agonists and inhibitors of individual endocannabinoid degradative enzymes.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.forename: Robert E
authors.initials: RE
authors.lastname: Vann
authors.forename: D Matthew
authors.initials: DM
authors.lastname: Walentiny
authors.forename: Lamont
authors.initials: L
authors.lastname: Booker
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: James J
authors.initials: JJ
authors.lastname: Burston
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sim-Selley
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D002265:Carboxylic Ester Hydrolases; D063388:Endocannabinoids; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D010879:Piperazines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C000592052:JZL195; C094503:glyceryl 2-arachidonate; C021859:neurotoxic esterase; C078814:anandamide