Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

Sciolino, Natale R.; Zhou, Wenyi; Hohmann, Andrea G.

doi:10.1016/j.phrs.2011.04.010

Cited by 179Cannabis and Cannabinoid ResearchStress Responses and CortisolMedicinal Plant Extracts Effects

Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

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Sciolino, Natale R., Zhou, Wenyi, Hohmann, Andrea G.·2011·Pharmacological Research

DOI 10.1016/j.phrs.2011.04.010PMC PMC3140828

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Abstract

Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1-8mg/kg), the benzodiazepine diazepam (1mg/kg), the cannabinoid CB(1) receptor antagonist rimonabant (1mg/kg), or JZL184 (8mg/kg) coadministered with rimonabant (1mg/kg). JZL184 (8mg/kg) produced anxiolytic-like effects (i.e., increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB(1). Anxiolytic effects of JZL184 were preserved following chronic (8mg/kg per day×6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5mg/kg i.p.) 24 or 72h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.

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Systemically administered MAGL inhibitors acutely reduce anxiety-like behavior.
“In this context, systemically administered MAGL inhibitors have been shown to acutely reduce anxiety-like behavior [75–78]”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [78]

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Authors: Sciolino, N. R., Zhou, W., & Hohmann, A. G.
Affiliations: University of Georgia (US)
Indiana University Bloomington (US)
Corresponding author: Hohmann, Andrea G.
ORCID: Sciolino, Natale R.
Zhou, Wenyi
Hohmann, Andrea G.
Venue: Pharmacological Research
Publisher: Elsevier BV
Published: 2011-09
Volume: 64
Issue: 3
Pages: 226-234
ISSN: 1043-6618 (ISSN-L)
DOI: 10.1016/j.phrs.2011.04.010
PMC: PMC3140828
OpenAlex: W2062462607
Cited by: 179
References: 79
Citations by year: 2026: 7 · 2025: 11 · 2024: 2 · 2023: 8 · 2022: 6 · 2021: 14 · 2020: 9 · 2019: 5 · 2018: 12 · 2017: 10 · 2016: 8 · 2015: 26 · 2014: 19 · 2013: 20 · 2012: 15
FWCI: 14.05
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Pharmacological Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIDA Diversity Supplement (DA021644S1)
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plant Extracts Effects
Keywords: JZL184, monoacylglycerol lipase inhibition, 2-arachidonoylglycerol, endocannabinoid system, anxiety, elevated plus maze, CB1 receptor, rimonabant, diazepam, WIN 55,212-2, stress responsiveness, chronic drug administration, emotion regulation, cannabinoid receptor agonists
MeSH terms: Rimonabant, Animals, Anxiety, Arachidonic Acids, Catalepsy, Diazepam, Glycerides, Male, Monoacylglycerol Lipases, Piperidines, Pyrazoles, Anti-Anxiety Agents, Signal Transduction, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Rats, Benzodioxoles, Cannabinoid Receptor Modulators, Endocannabinoids

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Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

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