title: Selective depression by general anesthetics of glutamate versus GABA release from isolated cortical nerve terminals.
abstract: The role of presynaptic mechanisms in general anesthetic depression of excitatory glutamatergic neurotransmission and facilitation of GABA-mediated inhibitory neurotransmission is unclear. A dual isotope method allowed simultaneous comparisons of the effects of a representative volatile (isoflurane) and intravenous (propofol) anesthetic on the 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 determined by superfusion with pulses of 30 mM K(+) or 1 mM 4-aminopyridine (4AP) in the absence or presence of 1.9 mM free Ca(2+). Isoflurane maximally inhibited Ca(2+)-dependent 4AP-evoked L-[(3)H]glutamate release (99 +/- 8% inhibition) to a greater extent than [(14)C]GABA release (74 +/- 6% inhibition; P = 0.023). Greater inhibition of L-[(3)H]glutamate versus [(14)C]GABA release was also observed for the Na(+) channel antagonists tetrodotoxin (99 +/- 4 versus 63 +/- 5% inhibition; P < 0.001) and riluzole (84 +/- 5 versus 52 +/- 12% inhibition; P = 0.041). Propofol did not differ in its maximum inhibition of Ca(2+)-dependent 4AP-evoked L-[(3)H]glutamate release (76 +/- 12% inhibition) compared with [(14)C]GABA (84 +/- 31% inhibition; P = 0.99) release. Neither isoflurane (1 mM) nor propofol (15 microM) affected K(+)-evoked release, consistent with a molecular target upstream of the synaptic vesicle exocytotic machinery or voltage-gated Ca(2+) channels coupled to transmitter release. These findings support selective presynaptic depression of excitatory versus inhibitory neurotransmission by clinical concentrations of isoflurane, probably as a result of Na(+) channel blockade.
authors.affiliation: Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, 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; D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018681:Anesthetics, General; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D015761:4-Aminopyridine; D007530:Isoflurane; D011188:Potassium