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Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels of the rat.

Abstract

Our group has described previously that the endogenous cannabinoid anandamide induces sleep. The hydrolysis of this lipid involves the activity of the fatty acid amide hydrolase (FAAH), which additionally catalyzes the degradation of the satiety factor oleoylethanolamide and the analgesic-inducing lipid palmitoylethanolamide. It has been demonstrated that the inhibition of the FAAH by URB597 increases levels of anandamide, oleoylethanolamide and palmitoylethanolamide in the brain of rats. In order to determinate the physiological properties of the FAAH inhibition on the sleep modulation, we report the pharmacological effects on the sleep-wake cycle of the rat after i.c.v. administrations of URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl). Separate unilateral i.c.v. injections of 3 compounds during the lights-on period, increased wakefulness and decreased slow wave (SW) sleep in rats in a dose-dependent fashion. We additionally found out that, compared to controls, c-Fos immunoreactivity in hypothalamus and dorsal raphe nucleus was increased in rats that received URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl, i.c.v.). Next, we found that after an injection of the compounds, levels of dopamine were increased whereas extracellular levels of levodopa (l-DOPA) were decreased. These findings indicate that that inhibition of the FAAH, via URB597, modulates waking. These effects were mimicked separately by the administration of oleoylethanolamide or palmitoylethanolamide. The alertness induced by the compounds tested here activated wake-promoting brain regions and they also induced the release of dopamine. Our results suggest that FAAH activity as well as two molecules that are catalyzed by this enzyme, oleoylethanolamide and palmitoylethanolamide, participate in the regulation of the waking state. Alternative approaches to treat sleep disorders such as excessive somnolence might consider the use of the URB597, oleoylethanolamide or palmitoylethanolamide since all compounds enhance waking.

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  • Authors+Show Affiliations

    ,

    Depto de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México. emurillo@ifc.unam.mx

    , , ,

    Source

    European journal of pharmacology 562:1-2 2007 May 07 pg 82-91

    MeSH

    Amidohydrolases
    Analgesics
    Animals
    Benzamides
    Carbamates
    Dopamine
    Dose-Response Relationship, Drug
    Endocannabinoids
    Ethanolamines
    Hippocampus
    Injections, Intraventricular
    Levodopa
    Male
    Microdialysis
    Nucleus Accumbens
    Oleic Acids
    Palmitic Acids
    Proto-Oncogene Proteins c-fos
    Raphe Nuclei
    Rats
    Rats, Wistar
    Sleep
    Time Factors
    Wakefulness

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17336288

    Citation

    Murillo-Rodríguez, Eric, et al. "Effects of the Fatty Acid Amide Hydrolase Inhibitor URB597 On the Sleep-wake Cycle, c-Fos Expression and Dopamine Levels of the Rat." European Journal of Pharmacology, vol. 562, no. 1-2, 2007, pp. 82-91.
    Murillo-Rodríguez E, Vázquez E, Millán-Aldaco D, et al. Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels of the rat. Eur J Pharmacol. 2007;562(1-2):82-91.
    Murillo-Rodríguez, E., Vázquez, E., Millán-Aldaco, D., Palomero-Rivero, M., & Drucker-Colin, R. (2007). Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels of the rat. European Journal of Pharmacology, 562(1-2), pp. 82-91.
    Murillo-Rodríguez E, et al. Effects of the Fatty Acid Amide Hydrolase Inhibitor URB597 On the Sleep-wake Cycle, c-Fos Expression and Dopamine Levels of the Rat. Eur J Pharmacol. 2007 May 7;562(1-2):82-91. PubMed PMID: 17336288.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels of the rat. AU - Murillo-Rodríguez,Eric, AU - Vázquez,Edgar, AU - Millán-Aldaco,Diana, AU - Palomero-Rivero,Marcela, AU - Drucker-Colin,René, Y1 - 2007/02/08/ PY - 2006/08/22/received PY - 2007/01/18/revised PY - 2007/01/25/accepted PY - 2007/3/6/pubmed PY - 2007/6/15/medline PY - 2007/3/6/entrez SP - 82 EP - 91 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 562 IS - 1-2 N2 - Our group has described previously that the endogenous cannabinoid anandamide induces sleep. The hydrolysis of this lipid involves the activity of the fatty acid amide hydrolase (FAAH), which additionally catalyzes the degradation of the satiety factor oleoylethanolamide and the analgesic-inducing lipid palmitoylethanolamide. It has been demonstrated that the inhibition of the FAAH by URB597 increases levels of anandamide, oleoylethanolamide and palmitoylethanolamide in the brain of rats. In order to determinate the physiological properties of the FAAH inhibition on the sleep modulation, we report the pharmacological effects on the sleep-wake cycle of the rat after i.c.v. administrations of URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl). Separate unilateral i.c.v. injections of 3 compounds during the lights-on period, increased wakefulness and decreased slow wave (SW) sleep in rats in a dose-dependent fashion. We additionally found out that, compared to controls, c-Fos immunoreactivity in hypothalamus and dorsal raphe nucleus was increased in rats that received URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl, i.c.v.). Next, we found that after an injection of the compounds, levels of dopamine were increased whereas extracellular levels of levodopa (l-DOPA) were decreased. These findings indicate that that inhibition of the FAAH, via URB597, modulates waking. These effects were mimicked separately by the administration of oleoylethanolamide or palmitoylethanolamide. The alertness induced by the compounds tested here activated wake-promoting brain regions and they also induced the release of dopamine. Our results suggest that FAAH activity as well as two molecules that are catalyzed by this enzyme, oleoylethanolamide and palmitoylethanolamide, participate in the regulation of the waking state. Alternative approaches to treat sleep disorders such as excessive somnolence might consider the use of the URB597, oleoylethanolamide or palmitoylethanolamide since all compounds enhance waking. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17336288/Effects_of_the_fatty_acid_amide_hydrolase_inhibitor_URB597_on_the_sleep_wake_cycle_c_Fos_expression_and_dopamine_levels_of_the_rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)00141-0 DB - PRIME DP - Unbound Medicine ER -