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Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.

Abstract

Cannabinoids have long been shown to have a range of potential therapeutic effects, including antiemetic actions, analgesia, and anxiolysis. However, psychomimetic and memory disruptive side effects, as well as the potential for abuse and dependence, have restricted their clinical development. Endogenous cannabinoids (i.e., endocannabinoids; eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. AEA and 2-AG are rapidly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Accordingly, inhibition of each enzyme increases brain levels of the appropriate eCB. Although FAAH inhibition has been established to decrease anxiety-like behavior, the role of 2-AG has been difficult to ascertain until the recent synthesis of JZL184, a potent and selective MAGL inhibitor. In the present study, we investigated the effects of inhibiting FAAH or MAGL on anxiety-like behavior in marble burying, a model of repetitive, compulsive behaviors germane to anxiety disorders such as obsessive-compulsive disorder. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the benzodiazepine diazepam decreased marble burying at doses that did not affect locomotor activity. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, did not consistently reduce marble burying without also eliciting profound decreases in locomotor behavior. The CB1 cannabinoid receptor antagonist rimonabant blocked the reduction in marble burying caused by FAAH and MAGL inhibitors, but not by diazepam, indicating a CB1 receptor mechanism of action. These data indicate that elevation of AEA or 2-AG reduces marble burying behavior and suggest that their catabolic enzymes represent potential targets for the development of new classes of pharmacotherapeutics to treat anxiety-related disorders.

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    ,

    Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA. sgkinsey@vcu.edu

    , , ,

    Source

    MeSH

    Amidohydrolases
    Animals
    Anti-Anxiety Agents
    Anxiety Disorders
    Benzodioxoles
    Cannabinoid Receptor Modulators
    Diazepam
    Disease Models, Animal
    Dronabinol
    Endocannabinoids
    Enzyme Inhibitors
    Male
    Mice
    Mice, Inbred C57BL
    Monoacylglycerol Lipases
    Obsessive-Compulsive Disorder
    Piperidines
    Pyrazoles
    Receptor, Cannabinoid, CB1
    Rimonabant

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    21145341

    Citation

    * When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay. AU - Kinsey,Steven G, AU - O'Neal,Scott T, AU - Long,Jonathan Z, AU - Cravatt,Benjamin F, AU - Lichtman,Aron H, Y1 - 2010/12/08/ PY - 2010/10/19/received PY - 2010/11/29/revised PY - 2010/12/02/accepted PY - 2010/12/15/entrez PY - 2010/12/15/pubmed PY - 2011/5/5/medline SP - 21 EP - 7 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol. Biochem. Behav. VL - 98 IS - 1 N2 - Cannabinoids have long been shown to have a range of potential therapeutic effects, including antiemetic actions, analgesia, and anxiolysis. However, psychomimetic and memory disruptive side effects, as well as the potential for abuse and dependence, have restricted their clinical development. Endogenous cannabinoids (i.e., endocannabinoids; eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. AEA and 2-AG are rapidly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Accordingly, inhibition of each enzyme increases brain levels of the appropriate eCB. Although FAAH inhibition has been established to decrease anxiety-like behavior, the role of 2-AG has been difficult to ascertain until the recent synthesis of JZL184, a potent and selective MAGL inhibitor. In the present study, we investigated the effects of inhibiting FAAH or MAGL on anxiety-like behavior in marble burying, a model of repetitive, compulsive behaviors germane to anxiety disorders such as obsessive-compulsive disorder. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the benzodiazepine diazepam decreased marble burying at doses that did not affect locomotor activity. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, did not consistently reduce marble burying without also eliciting profound decreases in locomotor behavior. The CB1 cannabinoid receptor antagonist rimonabant blocked the reduction in marble burying caused by FAAH and MAGL inhibitors, but not by diazepam, indicating a CB1 receptor mechanism of action. These data indicate that elevation of AEA or 2-AG reduces marble burying behavior and suggest that their catabolic enzymes represent potential targets for the development of new classes of pharmacotherapeutics to treat anxiety-related disorders. SN - 1873-5177 UR - https://www.unboundmedicine.com/medline/citation/21145341/abstract/Inhibition_of_endocannabinoid_catabolic_enzymes_elicits_anxiolytic_like_effects_in_the_marble_burying_assay_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-3057(10)00365-5 DB - PRIME DP - Unbound Medicine ER -