Journal Article

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

R. I. Westphalen, R. S. Gomez and H. C. Hemmings

in BJA: British Journal of Anaesthesia

Published on behalf of the British Journal of Anaesthesia

Volume 102, issue 3, pages 355-360
Published in print March 2009 | ISSN: 0007-0912
Published online February 2009 | e-ISSN: 1471-6771 | DOI: https://dx.doi.org/10.1093/bja/aen387
Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

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Background

Inhaled anaesthetics (IAs) produce multiple dose-dependent behavioural effects including amnesia, hypnosis, and immobility in response to painful stimuli that are mediated by distinct anatomical, cellular, and molecular mechanisms. Amnesia is produced at lower anaesthetic concentrations compared with hypnosis or immobility. Nicotinic acetylcholine receptors (nAChRs) modulate hippocampal neural network correlates of memory and are highly sensitive to IAs. Activation of hippocampal nAChRs stimulates the release of norepinephrine (NE), a neurotransmitter implicated in modulating hippocampal synaptic plasticity. We tested the hypothesis that IAs disrupt hippocampal synaptic mechanisms critical to memory by determining the effects of isoflurane on NE release from hippocampal nerve terminals.

Methods

Isolated nerve terminals prepared from adult male Sprague–Dawley rat hippocampus were radiolabelled with [3H]NE and either [14C]GABA or [14C]glutamate and superfused at 37°C. Release evoked by a 2 min pulse of 100 µM nicotine or 5 µM 4-aminopyridine was evaluated in the presence or absence of isoflurane and/or selective antagonists.

Results

Nicotine-evoked NE release from rat hippocampal nerve terminals was nAChR- and Ca2+-dependent, involved both α7 and non-α7 subunit-containing nAChRs, and was partially dependent on voltage-gated Na+ channel activation based on sensitivities to various antagonists. Isoflurane inhibited nicotine-evoked NE release (IC50=0.18 mM) more potently than depolarization-evoked NE release (IC50=0.27 mM, P=0.014), consistent with distinct presynaptic mechanisms of IA action.

Conclusions

Inhibition of hippocampal nAChR-dependent NE release by subanaesthetic concentrations of isoflurane supports a role in IA-induced amnesia.

Keywords: anaesthetics volatile, isoflurane; brain, anaesthesia, molecular effects; brain, hippocampus; ions, ion channels, ligand-gated; nerve, neurotransmitters

Journal Article.  2964 words.  Illustrated.

Subjects: Anaesthetics

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