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Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.
AAPS J 2009; 11(2):342-52AJ

Abstract

Abstinence symptoms in cannabis-dependent individuals are believed to contribute to the maintenance of regular marijuana use. However, there are currently no medications approved by the FDA to treat cannabis-related disorders. The only treatment currently shown consistently to alleviate cannabinoid withdrawal in both animals and humans is substitution therapy using the psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol (THC). However, new genetic and pharmacological tools are available to increase endocannabinoid levels by targeting fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the enzymes responsible for the degradation of the endogenous cannabinoid ligands anandamide and 2-arachidonoylglycerol, respectively. In the present study, we investigated whether increasing endogenous cannabinoids levels, through the use of FAAH (-/-) mice as well as the FAAH inhibitor URB597 or the MAGL inhibitor JZL184, would reduce the intensity of withdrawal signs precipitated by the CB(1) receptor antagonist rimonabant in THC-dependent mice. Strikingly, acute administration of either URB597 or JZL184 significantly attenuated rimonabant-precipitated withdrawal signs in THC-dependent mice. In contrast, FAAH (-/-) mice showed identical withdrawal responses as wild-type mice under a variety of conditions, suggesting that the absence of this enzyme across the development of dependence and during rimonabant challenge does not affect withdrawal responses. Of importance, subchronic administration of URB597 did not lead to cannabinoid dependence and neither URB597 nor JZL184 impaired rotarod motor coordination. These results support the concept of targeting endocannabinoid metabolizing enzymes as a promising treatment for cannabis withdrawal.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, P.O. Box 980613, Richmond, Virginia 23298-0613, USA.No 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

19430909

Citation

Schlosburg, Joel E., et al. "Inhibitors of Endocannabinoid-metabolizing Enzymes Reduce Precipitated Withdrawal Responses in THC-dependent Mice." The AAPS Journal, vol. 11, no. 2, 2009, pp. 342-52.
Schlosburg JE, Carlson BL, Ramesh D, et al. Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J. 2009;11(2):342-52.
Schlosburg, J. E., Carlson, B. L., Ramesh, D., Abdullah, R. A., Long, J. Z., Cravatt, B. F., & Lichtman, A. H. (2009). Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. The AAPS Journal, 11(2), pp. 342-52. doi:10.1208/s12248-009-9110-7.
Schlosburg JE, et al. Inhibitors of Endocannabinoid-metabolizing Enzymes Reduce Precipitated Withdrawal Responses in THC-dependent Mice. AAPS J. 2009;11(2):342-52. PubMed PMID: 19430909.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AU - Schlosburg,Joel E, AU - Carlson,Brittany L A, AU - Ramesh,Divya, AU - Abdullah,Rehab A, AU - Long,Jonathan Z, AU - Cravatt,Benjamin F, AU - Lichtman,Aron H, Y1 - 2009/05/09/ PY - 2009/02/02/received PY - 2009/04/20/accepted PY - 2009/5/12/entrez PY - 2009/5/12/pubmed PY - 2009/8/13/medline SP - 342 EP - 52 JF - The AAPS journal JO - AAPS J VL - 11 IS - 2 N2 - Abstinence symptoms in cannabis-dependent individuals are believed to contribute to the maintenance of regular marijuana use. However, there are currently no medications approved by the FDA to treat cannabis-related disorders. The only treatment currently shown consistently to alleviate cannabinoid withdrawal in both animals and humans is substitution therapy using the psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol (THC). However, new genetic and pharmacological tools are available to increase endocannabinoid levels by targeting fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the enzymes responsible for the degradation of the endogenous cannabinoid ligands anandamide and 2-arachidonoylglycerol, respectively. In the present study, we investigated whether increasing endogenous cannabinoids levels, through the use of FAAH (-/-) mice as well as the FAAH inhibitor URB597 or the MAGL inhibitor JZL184, would reduce the intensity of withdrawal signs precipitated by the CB(1) receptor antagonist rimonabant in THC-dependent mice. Strikingly, acute administration of either URB597 or JZL184 significantly attenuated rimonabant-precipitated withdrawal signs in THC-dependent mice. In contrast, FAAH (-/-) mice showed identical withdrawal responses as wild-type mice under a variety of conditions, suggesting that the absence of this enzyme across the development of dependence and during rimonabant challenge does not affect withdrawal responses. Of importance, subchronic administration of URB597 did not lead to cannabinoid dependence and neither URB597 nor JZL184 impaired rotarod motor coordination. These results support the concept of targeting endocannabinoid metabolizing enzymes as a promising treatment for cannabis withdrawal. SN - 1550-7416 UR - https://www.unboundmedicine.com/medline/citation/19430909/Inhibitors_of_endocannabinoid_metabolizing_enzymes_reduce_precipitated_withdrawal_responses_in_THC_dependent_mice_ L2 - https://dx.doi.org/10.1208/s12248-009-9110-7 DB - PRIME DP - Unbound Medicine ER -