OLEAMIDE POTENTIATES BENZODIAZEPINE-SENSITIVE GAMMA-AMINOBUTYRIC-ACIDRECEPTOR ACTIVITY BUT DOES NOT ALTER MINIMUM ALVEOLAR ANESTHETIC CONCENTRATION

A naturally occurring brain lipid, cis-9,10-octadeceamide-oleamide (OA ) is found in increased concentrations in the cerebrospinal fluid of s leep-deprived cats, which suggests that it may be an endogenous sleep- inducing substance. We studied the effects of this fatty-add derivativ e on the function of cloned gamma-aminobutyric add (GABA(A)) receptors expressed in Xenopus oocytes. Oocytes were injected with cRNA synthes ized in vitro to express simple GABA(A) receptors (alpha 1 beta 1, alp ha 3 beta 1, alpha 5 beta 1, and alpha 1 beta 2 subunit combinations) and receptors in which the GABA-induced chloride currents were potenti ated in the presence of benzodiazepines (alpha 1 beta 1 gamma 2s and a lpha 1 beta 2 gamma 2s subunit combinations). OA only produced signifi cant potentiation of the peak Cl- current when applied with GABA to be nzodiazepine-sensitive GABA(A) receptors. The peak currents of the sim ple GABA(A) receptors in the presence of OA were either unaffected or slightly inhibited by OA, but the overall mean currents were not signi ficantly altered. Oleic add was also capable of potentiating benzodiaz epine-sensitive GABA(A) receptor function. The function of other ligan d-gated ion channels, such as the N-methyl-D-aspartate receptor (NR1 NR2A or 2C) and the 5-HT3 receptor expressed in Xenopus oocytes, were unaffected by OA. Sprague-Dawley rats receiving intraperitoneal injec tions of oleamide (10, 20, or 100 mg/kg) showed no change in the minim um alveolar anesthetic concentration (MAC) of desflurane required to a bolish movement in response to noxious (tail clamp) stimulation (contr ol MAC 6.48% +/- 1.28% atm; 100 mg/kg OA MAC 7.05% +/- 0.42% atm). The se results reinforce the view that oleyl compounds may be natural modu lators of inhibitory ion channel function, but that these effects cont ribute little to the central nervous system depression produced by vol atile anesthetics as measured by MAC. Implications: The putative sleep inducing substance, oleamide, potentiates benzodiazepine sensitive ga mma-aminobutyric acid receptor function but does not alter desflurane minimum alveolar anesthetic concentration in rats.