Abstract
Endocannabinoid (eCB) signaling mediates depolarization-induced suppression of excitation (DSE) and inhibition (DSI), two prominent forms of retrograde synaptic depression. N-Arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), two known eCBs, are degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Selective blockade of FAAH and MAGL is critical for determining the roles of the eCBs in DSE/DSI and understanding how their action is regulated. 4-Nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) is a recently developed, highly selective, and potent MAGL inhibitor that increases 2-AG but not AEA concentrations in mouse brain. Here, we report that JZL184 prolongs DSE in Purkinje neurons in cerebellar slices and DSI in CA1 pyramidal neurons in hippocampal slices. The effect of JZL184 on DSE/DSI is mimicked by the nonselective MAGL inhibitor methyl arachidonyl fluorophosphonate. In contrast, neither the selective FAAH inhibitor cyclohexylcarbamic acid 3′-carbomoylbiphenyl-3-yl ester (URB597) nor FAAH knockout has a significant effect on DSE/DSI. JZL184 produces greater enhancement of DSE/DSI in mouse neurons than that in rat neurons. The latter finding is consistent with biochemical studies showing that JZL184 is more potent in inhibiting mouse MAGL than rat MAGL. These results indicate that the degradation of 2-AG by MAGL is the rate-limiting step that determines the time course of DSE/DSI and that JZL184 is a useful tool for the study of 2-AG-mediated signaling.
- DSE, depolarization-induced suppression of excitation
- DSI, depolarization-induced suppression of inhibition
- ABPP, activity-based protein profiling
- 2-AG, 2-arachidonoylglycerol
- ACSF, artificial cerebrospinal fluid
- AEA, N-arachidonoylethanolamine
- AM251, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide
- CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione
- COX-2, cyclooxygenase-2
- d-AP-5, d-2-amino-5-phosphonovaleric acid
- DMSO, dimethyl sulfoxide
- eCB, endocannabinoid
- EPSCs, excitatory postsynaptic currents
- FAAH, fatty acid amide hydrolase
- IPSCs, inhibitory postsynaptic currents
- JZL184, 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate
- MAFP, methyl arachidonyl fluorophosphonate
- MAGL, monoacylglycerol lipase
- QX-314, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide
- URB597, cyclohexylcarbamic acid 3′-carbomoylbiphenyl-3-yl ester
- URB602, biphenyl-3-ylcarbamic acid cyclohexyl ester
- URB754, 6-methyl-2-[(4-methylphenyl)amino]-4H-3,1-benzoxazin-4-one.
Footnotes
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This work was supported by National Institutes of Health [Grants DA09155, DA017259, DA024741] (to C.J.H., B.F.C., and Q.S.L., respectively); the National Alliance for Research on Schizophrenia and Depression (to Q.S.L.); and the Advancing in a Healthier Wisconsin (to C.J.H. and Q.S.L.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.158162
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ABBREVIATIONS:
- Received June 26, 2009.
- Accepted August 7, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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