Prolonged monoacylglycerol lipase blockade causes equivalent cannabinoid receptor type 1 receptor-mediated adaptations in fatty acid amide hydrolase wild-type and knockout mice.
Abstract
Complementary genetic and pharmacological approaches to inhibit 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, enable the exploration of potential therapeutic applications and physiologic 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 those seen with inhibition of either enzyme alone. While cannabinoid receptor type 1 (CB1) 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 a high dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate; 40 mg/kg] given acutely or for 6 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 Δ(9)-tetrahydrocannabinol, decreases in CB1 receptor agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate 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.
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California schlos@scripps.edu.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.E.S., B.I.-J., D.R., R.A.A., Q.T., L.B., D.E.S., A.H.L.); Department of Psychology, West Virginia University, Morgantown, West Virginia (S.G.K.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology (J.Z.L., B.F.C.), and Committee on the Neurobiology of Addictive Disorders (J.E.S.), The Scripps Research Institute, La Jolla, California. MeSH
Adaptation, PhysiologicalAmidohydrolasesAnimalsBenzodioxolesDronabinolEndocannabinoidsMaleMiceMice, Inbred C57BLMice, KnockoutMonoacylglycerol LipasesPiperidinesReceptor, Cannabinoid, CB1
Pub Type(s)
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
