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

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 (α(1)β(2)γ(2L)) in oocytes (EC(50), 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 EC(50) (P<0.05) than GABA receptors (EC(50), 22.12±1.4 μM; 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 μM: P<0.001). Modulation was not voltage-dependent or associated with a shift in E(r). 4. 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. 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