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Department of Anesthesiology

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

TitleVolatile anesthetic effects on glutamate versus GABA release from isolated rat cortical nerve terminals: 4-aminopyridine-evoked release.
Publication TypeJournal Article
Year of Publication2006
AuthorsWestphalen RI, Hemmings HC
JournalJ Pharmacol Exp Ther
Volume316
Issue1
Pagination216-23
Date Published2006 Jan
ISSN0022-3565
Keywords4-Aminopyridine, Anesthetics, Inhalation, Animals, Cerebral Cortex, Dose-Response Relationship, Drug, Enflurane, gamma-Aminobutyric Acid, Glutamic Acid, Halothane, Isoflurane, Male, Nerve Endings, Neurotransmitter Agents, Potassium Channel Blockers, Presynaptic Terminals, Rats, Rats, Sprague-Dawley, Tetrodotoxin
Abstract

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-[(3)H]glutamate and [(14)C]GABA, and release was evoked by superfusion with pulses of 1 mM 4AP in the absence or presence of 1.9 mM free Ca(2+). All three volatile anesthetics inhibited Ca(2+)-dependent glutamate and GABA release; IC(50) values for glutamate were comparable to clinical concentrations (1-1.6x MAC), whereas IC(50) values for GABA release exceeded clinical concentrations (>2.2x MAC). All three volatile anesthetics inhibited both Ca(2+)-independent and Ca(2+)-dependent 4AP-evoked glutamate release equipotently, whereas inhibition of Ca(2+)-dependent 4AP-evoked GABA release was less potent than inhibition of Ca(2+)-independent GABA release. Inhibition of Ca(2+)-independent 4AP-evoked glutamate release was more potent than that of GABA release for isoflurane and enflurane but equipotent for halothane. Tetrodotoxin inhibited both Ca(2+)-independent and Ca(2+)-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 Ca(2+)-dependent 4AP-evoked glutamate release versus GABA release supports the hypothesis that reduced excitatory neurotransmission relative to inhibitory neurotransmission contributes to volatile anesthetic actions.

DOI10.1124/jpet.105.090662
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID16174800
Grant ListGM 58055 / GM / NIGMS NIH HHS / United States