Effects of barbiturates and ethanol on muscimol-induced release of [3H]-D-aspartate from rodent cerebellum.

The K+-stimulated release of [3H]-D-aspartate and [14C]-GABA from synaptosomal (P2) fractions prepared from rat cerebellum was studied. Muscimol enhanced the release of [3H]-D-aspartate by 60-75% and the release of [14C]-GABA by 20-35%. Muscimol also enhanced the release of [3H]-D-aspartate from P2 fractions prepared from swine and mouse cerebellum. Pentobarbital, an anesthetic barbiturate, had no effect on basal or K+-stimulated release of [3H]-D-aspartate or [14C]-GABA but potentiated the enhancement of [3H]-D-aspartate release by muscimol. The EC50 was approx. 50 microM. The S(-)-isomer of pentobarbital was more potent than the R(+)-isomer in potentiating the action of muscimol, in agreement with the anesthetic potencies of the isomers. Phenobarbital, an anticonvulsant barbiturate, enhanced release of [3H]-D-aspartate and [14C]-GABA in the absence of muscimol. In contrast, the convulsant barbiturate 5-ethyl-5-(2'-cyclohexylidene-ethyl)barbituric acid (CHEB) caused a significant increase in basal release of [3H]-D-aspartate and [14C]-GABA in the absence of muscimol. Diazepam and ethanol had no effect on the release of [3H]-D-aspartate and did not potentiate the action of muscimol. These experiments provide biochemical evidence for an enhancement of the action of GABA by anesthetic barbiturates. This effect appears to be mediated through a benzodiazepine-insensitive presynaptic GABA receptor.