The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo
Open accessAbstract
Δ 9-Tetrahydrocannabinol (THC), the psychoactive component of marijuana, and other direct cannabinoid receptor (CB1) agonists produce a number of neurobehavioral effects in mammals that range from the beneficial (analgesia) to the untoward (abuse potential). Why, however, this full spectrum of activities is not observed upon pharmacological inhibition or genetic deletion of either fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively, has remained unclear. Here, we describe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. Falling into this latter category was drug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were reversed by a CB1 antagonist. These data indicate that AEA and 2-AG signaling pathways interact to regulate specific behavioral processes in vivo, including those relevant to drug abuse, thus providing a potential mechanistic basis for the distinct pharmacological profiles of direct CB1 agonists and inhibitors of individual endocannabinoid degradative enzymes.
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2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain
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Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
Cravatt, B. F., Giang, D. K., Mayfield, S. P., Boger, D. L., Lerner, R. A., & Gilula, N. B. (1996) · Nature · doi:10.1038/384083a0 · Cited by 2,125
Self-citationModulation of anxiety through blockade of anandamide hydrolysis
Kathuria, S., Gaetani, S., Fegley, D., Valiño, F., Duranti, A., Tontini, A., Mor, M., Tarzia, G., Rana, G. L., Calignano, A., et al. (2003) · Nature Medicine · doi:10.1038/nm803 · Cited by 1,293
A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2-Arachidonoylglycerol
Blankman, J. L., Simon, G. M., & Cravatt, B. F. (2007) · Chemistry & Biology · doi:10.1016/j.chembiol.2007.11.006 · Cited by 1,177
Self-citationStructure and function of fatty acid amide hydrolase
McKinney, M. K., & Cravatt, B. F. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133450 · Cited by 680
Self-citationEnzymatic pathways that regulate endocannabinoid signaling in the nervous system
Ahn, K., McKinney, M. K., & Cravatt, B. F. (2008) · Chemical Reviews · doi:10.1021/cr0782067 · Cited by 529
Self-citationBlockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain
Kinsey, S. G., Long, J. Z., O’Neal, S. T., Abdullah, R. A., Poklis, J. L., Boger, D. L., Cravatt, B. F., & Lichtman, A. H. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.155465 · Cited by 330
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Cited by
Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation
Nomura, D. K., Morrison, B. E., Blankman, J. L., Long, J. Z., Kinsey, S. G., Marcondes, M. C. G., Ward, A. M., Hahn, Y. K., Lichtman, A. H., Conti, B., et al. (2011) · Science · doi:10.1126/science.1209200 · Cited by 727
Self-citationChronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system
Schlosburg, J. E., Blankman, J. L., Long, J. Z., Nomura, D. K., Pan, B., Kinsey, S. G., Nguyen, P. T., Ramesh, D., Booker, L., Burston, J. J., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2616 · Cited by 641
Self-citationMultiple Functions of Endocannabinoid Signaling in the Brain
Katona, I., & Freund, T. F. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062111-150420 · Cited by 630
Mitochondrial CB1 receptors regulate neuronal energy metabolism
Bénard, G., Massa, F., Puente, N., Lourenço, J., Bellocchio, L., Soria-Gómez, E., Matias, I., Delamarre, A., Metna-Laurent, M., Cannich, A., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3053 · Cited by 588
Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors
Johnson, D. S., Weerapana, E., & Cravatt, B. F. (2010) · Future Medicinal Chemistry · doi:10.4155/fmc.10.21 · Cited by 387
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Metadata
- Authors
- Long, J. Z., Nomura, D. K., Vann, R. E., Walentiny, D. M., Booker, L., Jin, X., Burston, J. J., Sim-Selley, L. J., Lichtman, A. H., Wiley, J. L., & Cravatt, B. F.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-12
- Volume
- 106
- Issue
- 48
- Pages
- 20270-20275
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2155801131
- Cited by
- 391
- References
- 8
- FWCI
- 17.08
- Type
- journal article
- Language
- en
- Open access
- green
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- Long, J. Z., Nomura, D. K., Vann, R. E., Walentiny, D. M., Booker, L., Jin, X., Burston, J. J., Sim-Selley, L. J., Lichtman, A. H., Wiley, J. L., & Cravatt, B. F. (2009). Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0909411106
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