We examine the sensitivity of GABAA and glycine receptors (same ionotropic superfamily) to oleamide. We address subunit‐dependence/modulatory mechanisms and analogies with depressant drugs. Oleamide modulated human GABAA currents (α1β2γ2L) in oocytes (EC50, 28.94±s.e.mean of 1.4 μM; Maximum 216%±35 of control, n=4). Modulation of human α1 glycine homo‐oligomers (significant), was less marked, with a lower EC50 (P<0.05) than GABA receptors (EC50, 22.12±1.4 μM; Maximum 171%±30, n=11). Only the hypnogenic cis geometric isomer enhanced glycine currents (without altering slope or maximal current, it reduced the glycine EC50 from 322 to 239 μM: P<0.001). Modulation was not voltage‐dependent or associated with a shift in Er. β1 containing GABAA receptors (insensitive to many depressant drugs) were positively modulated by oleamide. Oleamide efficacy was circa 2× greater at α1β1γ2L than α1β2γ2L (P=0.007). Splice variation in γ subunits did not alter oleamide sensitivity. cis‐9,10‐Octadecenoamide had no effect on the equilibrium binding of (3H)‐muscimol or (3H)‐EBOB to mouse brain membranes. It does not directly mimic GABA, or operate as a neurosteroid‐, benzodiazepine‐ or barbiturate‐like modulator of GABAA‐receptors. The transport of (3H)‐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. 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 GABAA complex. British Journal of Pharmacology (2002) 135, 1977–1987; doi:10.1038/sj.bjp.0704651
British Journal of Pharmacology – Wiley
Published: Apr 1, 2002
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