Volatile anesthetic effects on glutamate versus GABA release from isolated rat cortical nerve terminals: 4-Aminopyridine-evoked release

Inhibition of glutamatergic excitatory neurotransmission and potentiation of GABA-mediated inhibitory transmission are possible mechanisms involved in general anesthesia. We compared the effects of three volatile anesthetics (isoflurane, enflurane, or halothane) on 4-aminopyridine (4AP)-evoked release of glutamate and GABA from isolated rat cerebrocortical nerve terminals (synaptosomes). Synaptosomes were prelabeled with L-[H-3] glutamate and [C-14] GABA, and release was evoked by superfusion with pulses of 1 mM 4AP in the absence or presence of 1.9 mM free Ca2+. All three volatile anesthetics inhibited Ca2+-dependent glutamate and GABA release; IC50 values for glutamate were comparable to clinical concentrations (1-1.6x MAC), whereas IC50 values for GABA release exceeded clinical concentrations (>2.2 x MAC). All three volatile anesthetics inhibited both Ca2+-independent and Ca2+-dependent 4AP-evoked glutamate release equipotently, whereas inhibition of Ca2+-dependent 4AP-evoked GABA release was less potent than inhibition of Ca2+-independent GABA release. Inhibition of Ca2+-independent 4AP-evoked glutamate release was more potent than that of GABA release for isoflurane and enflurane but equipotent for halothane. Tetrodotoxin inhibited both Ca2+-independent and Ca2+-dependent 4AP-evoked glutamate and GABA release equipotently, consistent with Na+ channel involvement. In contrast to tetrodotoxin, volatile anesthetics exhibited selective effects on 4AP-evoked glutamate versus GABA release, consistent with distinct mechanisms of action. Preferential inhibition of Ca2+-dependent 4AP-evoked glutamate release versus GABA release supports the hypothesis that reduced excitatory neurotransmission relative to inhibitory neurotransmission contributes to volatile anesthetic actions.