• Cheryl L Limebeer, Rehab A Abdullah, Erin M Rock, Elizabeth Imhof, Kai Wang, Aron H Lichtman, and Linda A Parker.
• Department of Psychology and Neuroscience Graduate Program, University of Guelph, Guelph, ON, N1H 2W1, Canada.
• Psychopharmacology (Berl.). 2014 Feb 1; 231 (3): 603-12.

RationaleEnhancement of the endocannabinoid (EC) system may reduce anticipatory nausea (AN).ObjectivesThe experiments evaluated the potential of the dual fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase (MAGL) inhibitor, JZL195, on its own and combined with anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) to reduce contextually elicited gaping, a measure of AN in rats.MethodsFollowing four context lithium chloride (LiCl) pairings, rats were injected with vehicle (VEH) or JZL195 (10 mg kg(-1), intraperitoneally) 105 min before an injection of VEH, 2-AG (1.25 mg kg(-1)), or AEA (5.0 mg kg(-1)). Fifteen minutes later, all rats were placed in the LiCl-paired context for 5 min and in a different context for a 15-min locomotor test. Whole brains were extracted for EC analysis. The potential of the CB1 antagonist, SR141716, to reverse the suppression of AN by both JZL195 and AEA and of the CB2 antagonist, AM630, to reverse the suppression of AN by JZL195 was then evaluated.ResultsJZL195 suppressed gaping and elevated AEA, palmitoylethanolamine, and oleoylethanolamide. As the suppression of gaping was reversed by SR141716, but not by AM630, the effect was CB1 mediated. The suppressive effect of JZL195 on gaping, as well as elevation of AEA and 2-AG, was amplified by pretreatment with either AEA or 2-AG. On its own, AEA, but not 2-AG, also suppressed gaping-an effect that was also prevented by CB1 antagonism.ConclusionsJZL195 reduces AN primarily by acting as a FAAH inhibitor, but MAGL inhibition is also indicated.

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