@article {Westphalen216, author = {Robert I. Westphalen and Hugh C. Hemmings, Jr.}, title = {Volatile Anesthetic Effects on Glutamate versus GABA Release from Isolated Rat Cortical Nerve Terminals: 4-Aminopyridine-Evoked Release}, volume = {316}, number = {1}, pages = {216--223}, year = {2006}, doi = {10.1124/jpet.105.090662}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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-[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{\textendash}1.6{\texttimes} MAC), whereas IC50 values for GABA release exceeded clinical concentrations (\>2.2{\texttimes} 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/316/1/216}, eprint = {https://jpet.aspetjournals.org/content/316/1/216.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }