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Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress.

Abstract

BACKGROUND

The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents.

METHODS

We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression.

RESULTS

Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus.

CONCLUSIONS

URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, University of California, Irvine, California 92697-4260, USA.

    , , , , , , , ,

    Source

    Biological psychiatry 62:10 2007 Nov 15 pg 1103-10

    MeSH

    Amidohydrolases
    Animals
    Antidepressive Agents
    Behavior, Animal
    Benzamides
    Body Weight
    Brain
    Cannabinoid Receptor Modulators
    Carbamates
    Chronic Disease
    Disease Models, Animal
    Dose-Response Relationship, Drug
    Gene Expression Regulation
    Imipramine
    Lipid Metabolism
    Male
    Multivariate Analysis
    Rats
    Rats, Wistar
    Receptor, Cannabinoid, CB1
    Stress, Psychological
    Sucrose
    Time Factors

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    17511970

    Citation

    Bortolato, Marco, et al. "Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress." Biological Psychiatry, vol. 62, no. 10, 2007, pp. 1103-10.
    Bortolato M, Mangieri RA, Fu J, et al. Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry. 2007;62(10):1103-10.
    Bortolato, M., Mangieri, R. A., Fu, J., Kim, J. H., Arguello, O., Duranti, A., ... Piomelli, D. (2007). Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biological Psychiatry, 62(10), pp. 1103-10.
    Bortolato M, et al. Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress. Biol Psychiatry. 2007 Nov 15;62(10):1103-10. PubMed PMID: 17511970.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. AU - Bortolato,Marco, AU - Mangieri,Regina A, AU - Fu,Jin, AU - Kim,Janet H, AU - Arguello,Oliver, AU - Duranti,Andrea, AU - Tontini,Andrea, AU - Mor,Marco, AU - Tarzia,Giorgio, AU - Piomelli,Daniele, Y1 - 2007/05/23/ PY - 2006/08/02/received PY - 2006/11/18/revised PY - 2006/12/02/accepted PY - 2007/5/22/pubmed PY - 2008/2/2/medline PY - 2007/5/22/entrez SP - 1103 EP - 10 JF - Biological psychiatry JO - Biol. Psychiatry VL - 62 IS - 10 N2 - BACKGROUND: The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents. METHODS: We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression. RESULTS: Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus. CONCLUSIONS: URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain. SN - 0006-3223 UR - https://www.unboundmedicine.com/medline/citation/17511970/Antidepressant_like_activity_of_the_fatty_acid_amide_hydrolase_inhibitor_URB597_in_a_rat_model_of_chronic_mild_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(06)01552-6 DB - PRIME DP - Unbound Medicine ER -