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Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.
J Pharmacol Exp Ther. 2015 Feb; 352(2):195-207.JP

Abstract

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.) wiebelhausjm@vcu.edu.Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia (J.M.W., T.W.G., R.A.O., M.F.L., L.J.S.-S., R.A.A., R.E.V., S.S.N., A.H.L.); Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.); and RTI International, Research Triangle Park, North Carolina (J.L.W.).

Pub Type(s)

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

Language

eng

PubMed ID

25398241

Citation

Wiebelhaus, Jason M., et al. "Δ9-tetrahydrocannabinol and Endocannabinoid Degradative Enzyme Inhibitors Attenuate Intracranial Self-stimulation in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 352, no. 2, 2015, pp. 195-207.
Wiebelhaus JM, Grim TW, Owens RA, et al. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. J Pharmacol Exp Ther. 2015;352(2):195-207.
Wiebelhaus, J. M., Grim, T. W., Owens, R. A., Lazenka, M. F., Sim-Selley, L. J., Abdullah, R. A., Niphakis, M. J., Vann, R. E., Cravatt, B. F., Wiley, J. L., Negus, S. S., & Lichtman, A. H. (2015). Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. The Journal of Pharmacology and Experimental Therapeutics, 352(2), 195-207. https://doi.org/10.1124/jpet.114.218677
Wiebelhaus JM, et al. Δ9-tetrahydrocannabinol and Endocannabinoid Degradative Enzyme Inhibitors Attenuate Intracranial Self-stimulation in Mice. J Pharmacol Exp Ther. 2015;352(2):195-207. PubMed PMID: 25398241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. AU - Wiebelhaus,Jason M, AU - Grim,Travis W, AU - Owens,Robert A, AU - Lazenka,Matthew F, AU - Sim-Selley,Laura J, AU - Abdullah,Rehab A, AU - Niphakis,Micah J, AU - Vann,Robert E, AU - Cravatt,Benjamin F, AU - Wiley,Jenny L, AU - Negus,S Stevens, AU - Lichtman,Aron H, Y1 - 2014/11/14/ PY - 2014/11/16/entrez PY - 2014/11/16/pubmed PY - 2015/7/15/medline SP - 195 EP - 207 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 352 IS - 2 N2 - A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/25398241/Δ9_tetrahydrocannabinol_and_endocannabinoid_degradative_enzyme_inhibitors_attenuate_intracranial_self_stimulation_in_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=25398241 DB - PRIME DP - Unbound Medicine ER -