title: Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: R I
authors.initials: RI
authors.lastname: Westphalen
authors.forename: R S
authors.initials: RS
authors.lastname: Gomez
authors.forename: H C
authors.initials: HC
authors.lastname: Hemmings
mesh_terms: D015761:4-Aminopyridine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D018685:Anesthetics, Inhalation; D018722:Nicotinic Agonists; D026902:Potassium Channel Blockers; D011978:Receptors, Nicotinic; D009538:Nicotine; D015761:4-Aminopyridine; D007530:Isoflurane; D009638:Norepinephrine