RT Journal Article SR Electronic T1 Prolonged monoacylglycerol lipase blockade causes equivalent CB1-receptor mediated adaptations in FAAH wild type and knockout mice JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.114.212753 DO 10.1124/jpet.114.212753 A1 Joel E. Schlosburg A1 Steven G. Kinsey A1 Bogna Ignatowska-Jankowska A1 Divya Ramesh A1 Rehab A. Abdullah A1 Qing Tao A1 Lamont Booker A1 Jonathan Z. Long A1 Dana E. Selley A1 Benjamin F. Cravatt A1 Aron H. Lichtman YR 2014 UL http://jpet.aspetjournals.org/content/early/2014/05/21/jpet.114.212753.abstract AB Complementary genetic and pharmacological approaches to inhibit the monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), the primary hydrolytic enzymes of the respective endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), enable the exploration of potential therapeutic applications and physiological roles of these enzymes. Complete and simultaneous inhibition of both FAAH and MAGL produces greatly enhanced cannabimimetic responses, including increased antinociception, and other cannabimimetic effects, far beyond inhibition of either enzyme alone. While CB1 receptor function is maintained following chronic FAAH inactivation, prolonged excessive elevation of brain 2-AG levels, via MAGL inhibition, elicits both behavioral and molecular signs of cannabinoid tolerance and dependence. Here, we evaluated the consequences of high dose of the MAGL inhibitor, JZL184 (40 mg/kg) given acutely or for six days in FAAH (-/-) and (+/+) mice. While acute administration of JZL184 to FAAH (-/-) mice enhanced the magnitude of a subset of cannabimimetic responses, repeated JZL184 treatment led to tolerance to its antinociceptive effects, cross-tolerance to the pharmacological effects of THC, decreases in CB1 receptor agonist stimulated [35S]GTPĪ³S binding, and dependence as indicated by rimonabant-precipitated withdrawal behaviors, regardless of genotype. Together, these data suggest that simultaneous elevation of both endocannabinoids elicits enhanced cannabimimetic activity, but MAGL inhibition drives CB1 receptor functional tolerance and cannabinoid dependence.