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Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with Δ9-tetrahydrocannabinol in mice.
J Pharmacol Exp Ther. 2015 May; 353(2):261-8.JP

Abstract

Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibitors exert preclinical effects indicative of therapeutic potential (i.e., analgesia). However, the extent to which MAGL and FAAH inhibitors produce unwanted effects remains unclear. Here, FAAH and MAGL inhibition was examined separately and together in a Δ(9)-tetrahydrocannabinol (Δ(9)-THC; 5.6 mg/kg i.p.) discrimination assay predictive of subjective effects associated with cannabis use, and the relative contribution of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the prefrontal cortex, hippocampus, and caudate putamen to those effects was examined. Δ(9)-THC dose-dependently increased Δ(9)-THC appropriate responses (ED50 value = 2.8 mg/kg), whereas the FAAH inhibitors PF-3845 [N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide] and URB597 [(3'-​(aminocarbonyl)[1,​1'-​biphenyl]-​3-​yl)-​cyclohexylcarbamate] or a MAGL inhibitor JZL184 [4-​nitrophenyl-​4-​(dibenzo[d][1,​3]dioxol-​5-​yl(hydroxy)methyl)piperidine-​1-​carboxylate] alone did not substitute for the Δ(9)-THC discriminative stimulus. The nonselective FAAH/MAGL inhibitors SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] and JZL195 [4-​nitrophenyl 4-​(3-​phenoxybenzyl)piperazine-​1-​carboxylate] fully substituted for Δ(9)-THC with ED50 values equal to 2.4 and 17 mg/kg, respectively. Full substitution for Δ(9)-THC was also produced by a combination of JZL184 and PF-3845, but not by a combination of JZL184 and URB597 (i.e., 52% maximum). Cannabinoid receptor type 1 antagonist rimonabant attenuated the discriminative stimulus effects of Δ(9)-THC, SA-57, JZL195, and the combined effects of JZL184 and PF-3845. Full substitution for the Δ(9)-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. Overall, these results suggest that increasing both endogenous 2-AG and AEA produces qualitatively unique effects (i.e., the subjective effects of cannabis) that are not obtained from increasing either 2-AG or AEA separately.

Authors+Show Affiliations

Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (L.H., A.S., A.Z., A.G., L.R.M.); Department of Chemical Physiology, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (B.F.C.); and Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (A.H.L.).Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (L.H., A.S., A.Z., A.G., L.R.M.); Department of Chemical Physiology, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (B.F.C.); and Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (A.H.L.).Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (L.H., A.S., A.Z., A.G., L.R.M.); Department of Chemical Physiology, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (B.F.C.); and Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (A.H.L.).Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (L.H., A.S., A.Z., A.G., L.R.M.); Department of Chemical Physiology, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (B.F.C.); and Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (A.H.L.).Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (L.H., A.S., A.Z., A.G., L.R.M.); Department of Chemical Physiology, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (B.F.C.); and Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (A.H.L.).Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (L.H., A.S., A.Z., A.G., L.R.M.); Department of Chemical Physiology, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (B.F.C.); and Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (A.H.L.).Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas (L.H., A.S., A.Z., A.G., L.R.M.); Department of Chemical Physiology, Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California (B.F.C.); and Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (A.H.L.) mcmahonl@uthscsa.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25711338

Citation

Hruba, Lenka, et al. "Simultaneous Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Shares Discriminative Stimulus Effects With Δ9-tetrahydrocannabinol in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 353, no. 2, 2015, pp. 261-8.
Hruba L, Seillier A, Zaki A, et al. Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with Δ9-tetrahydrocannabinol in mice. J Pharmacol Exp Ther. 2015;353(2):261-8.
Hruba, L., Seillier, A., Zaki, A., Cravatt, B. F., Lichtman, A. H., Giuffrida, A., & McMahon, L. R. (2015). Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with Δ9-tetrahydrocannabinol in mice. The Journal of Pharmacology and Experimental Therapeutics, 353(2), 261-8. https://doi.org/10.1124/jpet.115.222836
Hruba L, et al. Simultaneous Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Shares Discriminative Stimulus Effects With Δ9-tetrahydrocannabinol in Mice. J Pharmacol Exp Ther. 2015;353(2):261-8. PubMed PMID: 25711338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with Δ9-tetrahydrocannabinol in mice. AU - Hruba,Lenka, AU - Seillier,Alexandre, AU - Zaki,Armia, AU - Cravatt,Benjamin F, AU - Lichtman,Aron H, AU - Giuffrida,Andrea, AU - McMahon,Lance R, Y1 - 2015/02/24/ PY - 2015/2/26/entrez PY - 2015/2/26/pubmed PY - 2015/5/27/medline SP - 261 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 353 IS - 2 N2 - Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibitors exert preclinical effects indicative of therapeutic potential (i.e., analgesia). However, the extent to which MAGL and FAAH inhibitors produce unwanted effects remains unclear. Here, FAAH and MAGL inhibition was examined separately and together in a Δ(9)-tetrahydrocannabinol (Δ(9)-THC; 5.6 mg/kg i.p.) discrimination assay predictive of subjective effects associated with cannabis use, and the relative contribution of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the prefrontal cortex, hippocampus, and caudate putamen to those effects was examined. Δ(9)-THC dose-dependently increased Δ(9)-THC appropriate responses (ED50 value = 2.8 mg/kg), whereas the FAAH inhibitors PF-3845 [N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide] and URB597 [(3'-​(aminocarbonyl)[1,​1'-​biphenyl]-​3-​yl)-​cyclohexylcarbamate] or a MAGL inhibitor JZL184 [4-​nitrophenyl-​4-​(dibenzo[d][1,​3]dioxol-​5-​yl(hydroxy)methyl)piperidine-​1-​carboxylate] alone did not substitute for the Δ(9)-THC discriminative stimulus. The nonselective FAAH/MAGL inhibitors SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] and JZL195 [4-​nitrophenyl 4-​(3-​phenoxybenzyl)piperazine-​1-​carboxylate] fully substituted for Δ(9)-THC with ED50 values equal to 2.4 and 17 mg/kg, respectively. Full substitution for Δ(9)-THC was also produced by a combination of JZL184 and PF-3845, but not by a combination of JZL184 and URB597 (i.e., 52% maximum). Cannabinoid receptor type 1 antagonist rimonabant attenuated the discriminative stimulus effects of Δ(9)-THC, SA-57, JZL195, and the combined effects of JZL184 and PF-3845. Full substitution for the Δ(9)-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. Overall, these results suggest that increasing both endogenous 2-AG and AEA produces qualitatively unique effects (i.e., the subjective effects of cannabis) that are not obtained from increasing either 2-AG or AEA separately. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/25711338/Simultaneous_inhibition_of_fatty_acid_amide_hydrolase_and_monoacylglycerol_lipase_shares_discriminative_stimulus_effects_with_Δ9_tetrahydrocannabinol_in_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=25711338 DB - PRIME DP - Unbound Medicine ER -