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.
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Anesthetics modulate presynaptic neurotransmitter release as an intrinsic component of their actions.
“A number of studies point to an important role for anesthetics in modulating presynaptic neurotransmitter release as an intrinsic component of their actions [78–80].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [80]
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Self-citationKoyanagi, Y., Torturo, C. L., Cook, D. C., Zhou, Z., & Hemmings, H. C. (2019) · British Journal of Anaesthesia · doi:10.1016/j.bja.2019.03.029 · Cited by 15 · see citing works
Self-citationSpeigel, I. A., & Hemmings, H. C. (2021) · British Journal of Anaesthesia · doi:10.1016/j.bja.2021.06.042 · Cited by 15 · see citing works
Self-citationPaired Assessment of Volatile Anesthetic Concentrations with Synaptic Actions Recorded In Vitro
McDougall, S. J., Peters, J. H., LaBrant, L. L., Wang, X., Koop, D. R., & Andresen, M. C. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003372 · Cited by 15 · see citing works
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Pharmacology of Inhaled Anesthetics
Hudson, A. E., Herold, K. F., & Hemmings, H. C. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-48110-6.00011-9 · Cited by 14 · see citing works
Self-citationRole of Voltage-Gated Sodium Channels in the Mechanism of Ether-Induced Unconsciousness
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Discrimination of auditory stimuli during isoflurane anesthesia.
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Molecular Targets of General Anesthetics in the Nervous System
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Brain burst suppression activity.
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Pharmacology of Inhaled Anesthetics
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Volatile anaesthetic effects on phospholipid binding to synaptotagmin 1, a presynaptic Ca2+ sensor.
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Self-citationPropofol Sedation Dose for MRI Examination in Autistic Children Compared with normal Children.
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Effects of propofol on presynaptic synapsin phosphorylation in the mouse brain in vivo
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Mechanisms of Action of Inhaled Volatile General Anesthetics: Unconsciousness at the Molecular Level
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Regulation of arousal by adenosine A1 and A2A receptors in the prefrontal cortex of C57BL/6J mouse
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Breaking the Limitations of ‘Milk’: Research Progress on New Derivatives of Propofol
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- Authors
- Westphalen, R. I., & Hemmings, H. C.
- Affiliations
- Cornell University (US)
- ORCID
- Hemmings, Hugh C.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 304
- Issue
- 3
- Pages
- 1188-1196
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2156798177
- Cited by
- 89
- References
- 50
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 9 · 2018: 1 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 1 · 2012: 5
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 58055, R01GM058055)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Keywords
- general anesthetics, isoflurane, propofol, presynaptic depression, glutamate release, GABA release, excitatory neurotransmission, inhibitory neurotransmission, synaptosomes, voltage-gated calcium channels, sodium channel blockade, tetrodotoxin, riluzole, 4-aminopyridine, synaptic vesicle exocytosis
- MeSH terms
- Animals, gamma-Aminobutyric Acid, Isoflurane, Male, Potassium, Synaptosomes, 4-Aminopyridine, Rats, Sprague-Dawley, Anesthetics, General, Glutamic Acid, Rats, In Vitro Techniques
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