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Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.
Proc Natl Acad Sci U S A 2009; 106(48):20270-5PN

Abstract

Delta(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.

Authors+Show Affiliations

The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19918051

Citation

Long, Jonathan Z., et al. "Dual Blockade of FAAH and MAGL Identifies Behavioral Processes Regulated By Endocannabinoid Crosstalk in Vivo." Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 48, 2009, pp. 20270-5.
Long JZ, Nomura DK, Vann RE, et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc Natl Acad Sci USA. 2009;106(48):20270-5.
Long, J. Z., Nomura, D. K., Vann, R. E., Walentiny, D. M., Booker, L., Jin, X., ... 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 of the United States of America, 106(48), pp. 20270-5. doi:10.1073/pnas.0909411106.
Long JZ, et al. Dual Blockade of FAAH and MAGL Identifies Behavioral Processes Regulated By Endocannabinoid Crosstalk in Vivo. Proc Natl Acad Sci USA. 2009 Dec 1;106(48):20270-5. PubMed PMID: 19918051.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. AU - Long,Jonathan Z, AU - Nomura,Daniel K, AU - Vann,Robert E, AU - Walentiny,D Matthew, AU - Booker,Lamont, AU - Jin,Xin, AU - Burston,James J, AU - Sim-Selley,Laura J, AU - Lichtman,Aron H, AU - Wiley,Jenny L, AU - Cravatt,Benjamin F, Y1 - 2009/11/16/ PY - 2009/11/18/entrez PY - 2009/11/18/pubmed PY - 2010/2/19/medline SP - 20270 EP - 5 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 106 IS - 48 N2 - Delta(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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/19918051/Dual_blockade_of_FAAH_and_MAGL_identifies_behavioral_processes_regulated_by_endocannabinoid_crosstalk_in_vivo_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=19918051 DB - PRIME DP - Unbound Medicine ER -