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BJA Advance Access published online on February 2, 2009
British Journal of Anaesthesia, doi:10.1093/bja/aen387
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2009. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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

R. I. Westphalen1,2, R. S. Gomez3 and H. C. Hemmings, Jr1,2,*

1 Department of Anesthesiology and
2 Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA
3 Faculdade de Medicina-UFMG, Avenida Alfredo Balena 190, Sala 203, Belo Horizonte-Minas Gerais, CEP 31340-300, Brazil

* Corresponding author. E-mail: hchemmi{at}med.cornell.edu

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 {alpha}7 and non-{alpha}7 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


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