title: Volatile anesthetic effects on glutamate versus GABA release from isolated rat cortical nerve terminals: 4-aminopyridine-evoked release.
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.
authors.affiliation: Department of Anesthesiology LC-203, Weill Medical College of Cornell University, Box 50, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Westphalen
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Hemmings
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004737:Enflurane / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D009411:Nerve Endings / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D018377:Neurotransmitter Agents; D026902:Potassium Channel Blockers; D018698:Glutamic Acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D004737:Enflurane; D015761:4-Aminopyridine; D007530:Isoflurane; D006221:Halothane