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Pharmacol Biochem Behav. 2014 Sep;124:153-9. doi: 10.1016/j.pbb.2014.05.022. Epub 2014 Jun 6.

The dual FAAH/MAGL inhibitor JZL195 has enhanced effects on endocannabinoid transmission and motor behavior in rats as compared to those of the MAGL inhibitor JZL184.

Author information

1
Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
2
Department of Pharmacology, Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: giuffrida@uthscsa.edu.

Abstract

The biological actions of the endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG) are terminated by enzymatic hydrolysis of these lipids via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. While several selective FAAH inhibitors have been developed and characterized in vitro and in vivo, none of the initial MAGL blockers have shown adequate potency and specificity for in vivo applications. More recently, a selective MAGL inhibitor, JZL184, has been shown to produce a long-lasting elevation of brain 2-AG, as well as cannabinoid-like behavioral responses in mice. However, its effectiveness in rats remains controversial. Indeed, although JZL184 can elicit behavioral responses that are mediated, at least in part, via activation of cannabinoid CB1 receptors, several reports indicate that this compound does not alter 2-AG levels in this species. In this study we compared the behavioral and neurochemical effects of JZL 184 with those of the dual FAAH/MAGL inhibitor JZL195, and showed that systemic administration of the former can selectively elevate brain 2-AG in rats and produce motor suppression through a CB1-independent mechanism. These findings indicate that, despite its lower potency against rat MAGL, JZL184 can be used to enhance 2-AG transmission and elicit behavioral responses in rodents.

KEYWORDS:

2-Arachidonoyl glycerol; Anandamide; CB1; Cannabinoid; Gas chromatography/mass spectrometry; Motor activity

PMID:
24911644
PMCID:
PMC4150743
DOI:
10.1016/j.pbb.2014.05.022
[Indexed for MEDLINE]
Free PMC Article

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