The sleep hormone oleamide modulates inhibitory ionotropic receptors in mammalian CNS in vitro

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. Oleamide modulated human GABA A currents (α 1 β 2 γ 2L ) in oocytes (EC 50 , 28.94±s.e.mean of 1.4 μ M ; Maximum 216%±35 of control, n =4). Modulation of human α1 glycine homo‐oligomers (significant), was less marked, with a lower EC 50 ( P <0.05) than GABA receptors (EC 50 , 22.12±1.4 μ M ; Maximum 171%±30, n =11). 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 μ M : P <0.001). Modulation was not voltage‐dependent or associated with a shift in E r . β1 containing GABA A receptors (insensitive to many depressant drugs) were positively modulated by oleamide. Oleamide efficacy was circa 2× greater at α 1 β 1 γ 2L than α 1 β 2 γ 2L ( 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 [ 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. 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. 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.British Journal of Pharmacology (2002) 135 , 1977–1987; doi: 10.1038/sj.bjp.0704651