Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.
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.
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.
Jason M
JM
Wiebelhaus
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.).
Travis W
TW
Grim
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.).
Robert A
RA
Owens
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.).
Matthew F
MF
Lazenka
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.).
Laura J
LJ
Sim-Selley
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.).
Rehab A
RA
Abdullah
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.).
Micah J
MJ
Niphakis
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.).
Robert E
RE
Vann
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.).
Benjamin F
BF
Cravatt
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.).
Jenny L
JL
Wiley
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.).
S Stevens
SS
Negus
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.).
Aron H
AH
Lichtman
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D004558:Electric Stimulation; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D012054:Reinforcement, Psychology; D012653:Self Stimulation; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D052117:Benzodioxoles; D001713:Biphenyl Compounds; D013759:Dronabinol; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D011726:Pyridinium Compounds; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C000596169:N,N'-dimethyl-4,4'-(biphenyl-2,1-ethenediyl)dipyridinium