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NEUROPHARMACOLOGY

Volatile Anesthetic Effects on Glutamate versus GABA Release from Isolated Rat Cortical Nerve Terminals: 4-Aminopyridine-Evoked Release

Departments of Anesthesiology and Pharmacology, Weill Medical College of Cornell University, New York, New York

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-[³H]glutamate and [¹⁴C]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 (>2.2x 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.

Address correspondence to: Dr. Hugh C. Hemmings, Jr., Department of Anesthesiology, LC-203, Box 50, 1300 York Avenue, New York, NY 10021. E-mail: hchemmi{at}med.cornell.edu

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