Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibitors exert preclinical effects indicative of therapeutic potential. In the present study, FAAH and MAGL inhibition was examined separately and together in a Δ9-tetrahydrocannabinol (Δ9-THC) discrimination assay predictive of subjective effects associated with cannabis use. The relative contribution of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) to those effects was also examined. Δ9-THC dose-dependently increased Δ9-THC appropriate responses, whereas FAAH or MAGL inhibitors administered alone did not substitute for the Δ9-THC discriminative stimulus. Nonselective FAAH/MAGL inhibitors fully substituted for Δ9-THC. Full substitution for the Δ9-THC discriminative stimulus occurred only when both 2-AG and AEA were significantly elevated, and the patterns of increased endocannabinoid content were similar among brain regions. The results suggest that increasing both endogenous 2-AG and AEA produces qualitatively unique effects that are not obtained from increasing either 2-AG or AEA separately.
See article at J Pharmacol Exp Ther 2015, 353:261–268.
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