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Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress.
Biol Psychiatry 2007; 62(10):1103-10BP

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.

Authors+Show Affiliations

Department of Pharmacology, University of California, Irvine, California 92697-4260, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

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 -