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Department of Anesthesiology

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

TitleNicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane.
Publication TypeJournal Article
Year of Publication2009
AuthorsWestphalen RI, Gomez RS, Hemmings HC
JournalBr J Anaesth
Date Published2009 Mar
Keywords4-Aminopyridine, Anesthetics, Inhalation, Animals, Dose-Response Relationship, Drug, Hippocampus, Isoflurane, Male, Nicotine, Nicotinic Agonists, Norepinephrine, Potassium Channel Blockers, Rats, Rats, Sprague-Dawley, Receptors, Nicotinic, Synapses, Tissue Culture Techniques

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 [(3)H]NE and either [(14)C]GABA or [(14)C]glutamate and superfused at 37 degrees C. Release evoked by a 2 min pulse of 100 microM nicotine or 5 microM 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 Ca(2+)-dependent, involved both alpha7 and non-alpha7 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 (IC(50)=0.18 mM) more potently than depolarization-evoked NE release (IC(50)=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.

Alternate JournalBr J Anaesth
PubMed ID19189985
PubMed Central IDPMC2642653
Grant ListGM58055 / GM / NIGMS NIH HHS / United States
R01 GM058055 / GM / NIGMS NIH HHS / United States