title: The sleep hormone oleamide modulates inhibitory ionotropic receptors in mammalian CNS in vitro.
abstract: 1. We examine the sensitivity of GABA(A) and glycine receptors (same ionotropic superfamily) to oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. 2. Oleamide modulated human GABA(A) currents (alpha(1)beta(2)gamma(2L)) in oocytes (EC(50), 28.94+/-s.e.mean of 1.4 microM; Maximum 216%+/-35 of control, n=4). Modulation of human alpha1 glycine homo-oligomers (significant), was less marked, with a lower EC(50) (P<0.05) than GABA receptors (EC(50), 22.12+/-1.4 microM; Maximum 171%+/-30, n=11). 3. Only the hypnogenic cis geometric isomer enhanced glycine currents (without altering slope or maximal current, it reduced the glycine EC(50) from 322 to 239 microM: P<0.001). Modulation was not voltage-dependent or associated with a shift in E(r). 4. beta 1 containing GABA(A) receptors (insensitive to many depressant drugs) were positively modulated by oleamide. Oleamide efficacy was circa 2x greater at alpha(1)beta(1)gamma(2L) than alpha(1)beta(2)gamma(2L) (P=0.007). Splice variation in gamma subunits did not alter oleamide sensitivity. 5. cis-9,10-Octadecenoamide had no effect on the equilibrium binding of [(3)H]-muscimol or [(3)H]-EBOB to mouse brain membranes. It does not directly mimic GABA, or operate as a neurosteroid-, benzodiazepine- or barbiturate-like modulator of GABA(A)-receptors. 6. The transport of [(3)H]-GABA into mouse brain synaptoneurosomes was unaffected by high micromolar concentrations of cis-9,10-octadecenoamide. Oleamide does not enhance GABA-ergic currents or prolong IPSCs by inhibiting GABA transport. 7. Oleamide is a non-selective modulator of inhibitory ionotropic receptors. The sleep lipid exerts its effects indirectly, or at a novel recognition site on the GABA(A) complex.
authors.affiliation: Institute of Pharmacy, Chemistry & Biomedical Sciences, School of Sciences, University of Sunderland, Wharncliffe Street, Sunderland SR1 3SD, UK.
authors.forename: Leanne
authors.initials: L
authors.lastname: Coyne
authors.forename: George
authors.initials: G
authors.lastname: Lees
authors.forename: Russell A
authors.initials: RA
authors.lastname: Nicholson
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Neufield
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D005998:Glycine / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009118:Muscimol / Q000378:metabolism; D009829:Oleic Acids / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000502:physiology*; D018009:Receptors, Glycine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012890:Sleep / Q000502:physiology; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006993:Hypnotics and Sedatives; D009829:Oleic Acids; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D014316:Tritium; C091518:1-(4-ethynylphenyl)-4-propyl-2,6,7-trioxabicyclo(2.2.2)octane; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C029407:oleylamide; D005998:Glycine