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The fatty acid amide hydrolase inhibitor URB 597: interactions with anandamide in rhesus monkeys.

Abstract

BACKGROUND AND PURPOSE

The fatty acid amide hydrolase inhibitor URB 597 increases brain anandamide levels, suggesting that URB 597 could enhance the behavioural effects of anandamide. The goal of the current study was to examine and characterize the in vivo pharmacology of URB 597 alone and in combination with anandamide and Δ⁹-tetrahydrocannabinol (Δ⁹ -THC) in two drug discrimination assays in rhesus monkeys.

EXPERIMENTAL APPROACH

The effects of URB 597 alone and in combination with anandamide were investigated in one group of monkeys (n= 4) that discriminated Δ⁹-THC (0.1 mg·kg⁻¹ i.v.) from vehicle, and in another group (n= 5) receiving chronic Δ⁹-THC (1 mg·kg⁻¹ 12 h⁻¹ s.c.) that discriminated the cannabinoid antagonist rimonabant (1 mg·kg⁻¹ i.v.).

KEY RESULTS

Intravenous anandamide fully substituted for, and had infra-additive effects with, Δ⁹-THC. URB 597 (up to 3.2 mg·kg⁻¹ i.v.) did not substitute for or modify the effects of Δ⁹-THC but markedly increased the potency (32-fold) and duration of action of anandamide. The rimonabant discriminative stimulus in Δ⁹-THC-treated monkeys (i.e. Δ⁹-THC withdrawal) was attenuated by both Δ⁹-THC (at doses larger than 1 mg·kg⁻¹ per 12 h) and anandamide but not by URB 597 (3.2 mg·kg⁻¹). URB 597 did not increase the potency of anandamide to attenuate the rimonabant-discriminative stimulus.

CONCLUSIONS AND IMPLICATIONS

URB 597 enhanced the behavioural effects of anandamide but not other CB₁ agonists. However, URB 597 did not significantly enhance the attenuation of Δ⁹-THC withdrawal induced by anandamide. Collectively, these data suggest that endogenous anandamide in primate brain does not readily mimic the behavioural effects of exogenously administered anandamide.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

    Source

    British journal of pharmacology 164:2b 2011 Sep pg 655-66

    MeSH

    Amidohydrolases
    Animals
    Arachidonic Acids
    Benzamides
    Carbamates
    Discrimination (Psychology)
    Dronabinol
    Drug Interactions
    Drug Therapy, Combination
    Endocannabinoids
    Female
    Macaca mulatta
    Male
    Piperidines
    Polyunsaturated Alkamides
    Pyrazoles

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    21449917

    Citation

    TY - JOUR T1 - The fatty acid amide hydrolase inhibitor URB 597: interactions with anandamide in rhesus monkeys. AU - Stewart,Jennifer L, AU - McMahon,Lance R, PY - 2011/4/1/entrez PY - 2011/4/1/pubmed PY - 2012/3/21/medline SP - 655 EP - 66 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 164 IS - 2b N2 - BACKGROUND AND PURPOSE: The fatty acid amide hydrolase inhibitor URB 597 increases brain anandamide levels, suggesting that URB 597 could enhance the behavioural effects of anandamide. The goal of the current study was to examine and characterize the in vivo pharmacology of URB 597 alone and in combination with anandamide and Δ⁹-tetrahydrocannabinol (Δ⁹ -THC) in two drug discrimination assays in rhesus monkeys. EXPERIMENTAL APPROACH: The effects of URB 597 alone and in combination with anandamide were investigated in one group of monkeys (n= 4) that discriminated Δ⁹-THC (0.1 mg·kg⁻¹ i.v.) from vehicle, and in another group (n= 5) receiving chronic Δ⁹-THC (1 mg·kg⁻¹ 12 h⁻¹ s.c.) that discriminated the cannabinoid antagonist rimonabant (1 mg·kg⁻¹ i.v.). KEY RESULTS: Intravenous anandamide fully substituted for, and had infra-additive effects with, Δ⁹-THC. URB 597 (up to 3.2 mg·kg⁻¹ i.v.) did not substitute for or modify the effects of Δ⁹-THC but markedly increased the potency (32-fold) and duration of action of anandamide. The rimonabant discriminative stimulus in Δ⁹-THC-treated monkeys (i.e. Δ⁹-THC withdrawal) was attenuated by both Δ⁹-THC (at doses larger than 1 mg·kg⁻¹ per 12 h) and anandamide but not by URB 597 (3.2 mg·kg⁻¹). URB 597 did not increase the potency of anandamide to attenuate the rimonabant-discriminative stimulus. CONCLUSIONS AND IMPLICATIONS: URB 597 enhanced the behavioural effects of anandamide but not other CB₁ agonists. However, URB 597 did not significantly enhance the attenuation of Δ⁹-THC withdrawal induced by anandamide. Collectively, these data suggest that endogenous anandamide in primate brain does not readily mimic the behavioural effects of exogenously administered anandamide. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21449917/abstract/The_fatty_acid_amide_hydrolase_inhibitor_URB_597:_interactions_with_anandamide_in_rhesus_monkeys_ L2 - https://doi.org/10.1111/j.1476-5381.2011.01388.x ER -