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Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice.
Neuropharmacology. 2017 Oct; 125:80-86.N

Abstract

Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Δ9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH-MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1-2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, 27709-2194, USA.The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.The Skaggs Institute for Chemical Biology, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: aron.lichtman@vcuhealth.org.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28673548

Citation

Owens, Robert A., et al. "Inhibition of the Endocannabinoid-regulating Enzyme Monoacylglycerol Lipase Elicits a CB1 Receptor-mediated Discriminative Stimulus in Mice." Neuropharmacology, vol. 125, 2017, pp. 80-86.
Owens RA, Mustafa MA, Ignatowska-Jankowska BM, et al. Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice. Neuropharmacology. 2017;125:80-86.
Owens, R. A., Mustafa, M. A., Ignatowska-Jankowska, B. M., Damaj, M. I., Beardsley, P. M., Wiley, J. L., Niphakis, M. J., Cravatt, B. F., & Lichtman, A. H. (2017). Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice. Neuropharmacology, 125, 80-86. https://doi.org/10.1016/j.neuropharm.2017.06.032
Owens RA, et al. Inhibition of the Endocannabinoid-regulating Enzyme Monoacylglycerol Lipase Elicits a CB1 Receptor-mediated Discriminative Stimulus in Mice. Neuropharmacology. 2017;125:80-86. PubMed PMID: 28673548.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice. AU - Owens,Robert A, AU - Mustafa,Mohammed A, AU - Ignatowska-Jankowska,Bogna M, AU - Damaj,M Imad, AU - Beardsley,Patrick M, AU - Wiley,Jenny L, AU - Niphakis,Micah J, AU - Cravatt,Benjamin F, AU - Lichtman,Aron H, Y1 - 2017/06/30/ PY - 2017/03/07/received PY - 2017/06/17/revised PY - 2017/06/29/accepted PY - 2017/7/5/pubmed PY - 2018/6/13/medline PY - 2017/7/5/entrez KW - 2-Arachidonoylglycerol (2-AG) KW - Alpha/beta-hydrolase domain 6 (ABHD6) KW - CP55,940 (PubChem CID: 104895) KW - Cannabinoid-1 (CB1) receptor KW - Diazepam (PubChem CID: 3016) KW - Discriminative stimulus KW - Drug discrimination KW - Endogenous cannabinoids KW - Fatty acid amide hydrolase (FAAH) KW - JZL184 (PubChem CID: 25021165) KW - KT182 (PubChem CID: 53364491) KW - MJN110 (PubChem CID: 71722059) KW - Monoacylglycerol lipase (MAGL) KW - N-arachidonoylethanolamine (anandamide, AEA) KW - Nicotine (PubChem CID: 24278591) KW - PF-3845 (PubChem CID: 25154867) KW - Rimonabant (PubChem CID: 104850) KW - SA-57 (PubChem CID: 44589122) KW - Valdecoxib (PubChem CID: 119607) SP - 80 EP - 86 JF - Neuropharmacology JO - Neuropharmacology VL - 125 N2 - Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Δ9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH-MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1-2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28673548/Inhibition_of_the_endocannabinoid_regulating_enzyme_monoacylglycerol_lipase_elicits_a_CB1_receptor_mediated_discriminative_stimulus_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(17)30305-2 DB - PRIME DP - Unbound Medicine ER -