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1.  Presynaptic inhibition of the release of multiple major central nervous system neurotransmitter types by the inhaled anaesthetic isoflurane 
BJA: British Journal of Anaesthesia  2012;110(4):592-599.
Background
Presynaptic effects of general anaesthetics are not well characterized. We tested the hypothesis that isoflurane exhibits transmitter-specific effects on neurotransmitter release from neurochemically and functionally distinct isolated mammalian nerve terminals.
Methods
Nerve terminals from adult male rat brain were prelabelled with [3H]glutamate and [14C]GABA (cerebral cortex), [3H]norepinephrine (hippocampus), [14C]dopamine (striatum), or [3H]choline (precursor of [3H]acetylcholine; striatum). Release evoked by depolarizing pulses of 4-aminopyridine (4AP) or elevated KCl was quantified using a closed superfusion system.
Results
Isoflurane at clinical concentrations (<0.7 mM; ∼2 times median anaesthetic concentration) inhibited Na+ channel-dependent 4AP-evoked release of the five neurotransmitters tested in a concentration-dependent manner. Isoflurane was a more potent inhibitor [expressed as IC50 (sem)] of glutamate release [0.37 (0.03) mM; P<0.05] compared with the release of GABA [0.52 (0.03) mM], norepinephrine [0.48 (0.03) mM], dopamine [0.48 (0.03) mM], or acetylcholine [0.49 (0.02) mM]. Inhibition of Na+ channel-independent release evoked by elevated K+ was not significant at clinical concentrations of isoflurane, with the exception of dopamine release [IC50=0.59 (0.03) mM].
Conclusions
Isoflurane inhibited the release of the major central nervous system neurotransmitters with selectivity for glutamate release, consistent with both widespread inhibition and nerve terminal-specific presynaptic effects. Glutamate release was most sensitive to inhibition compared with GABA, acetylcholine, dopamine, and norepinephrine release due to presynaptic specializations in ion channel expression, regulation, and/or coupling to exocytosis. Reductions in neurotransmitter release by volatile anaesthetics could contribute to altered synaptic transmission, leading to therapeutic and toxic effects involving all major neurotransmitter systems.
doi:10.1093/bja/aes448
PMCID: PMC3600942  PMID: 23213036
acetylcholine; γ-aminobutyric acid; anaesthetics; dopamine; exocytosis; glutamate; Na+ channels; nerve terminal; neurotransmitter release; norepinephrine
2.  Are anaesthetics toxic to the brain? 
It has been assumed that anaesthetics have minimal or no persistent effects after emergence from anaesthesia. However, general anaesthetics act on multiple ion channels, receptors, and cell signalling systems in the central nervous system to produce anaesthesia, so it should come as no surprise that they also have non-anaesthetic actions that range from beneficial to detrimental. Accumulating evidence is forcing the anaesthesia community to question the safety of general anaesthesia at the extremes of age. Preclinical data suggest that inhaled anaesthetics can have profound and long-lasting effects during key neurodevelopmental periods in neonatal animals by increasing neuronal cell death (apoptosis) and reducing neurogenesis. Clinical data remain conflicting on the significance of these laboratory data to the paediatric population. At the opposite extreme in age, elderly patients are recognized to be at an increased risk of postoperative cognitive dysfunction (POCD) with a well-recognized decline in cognitive function after surgery. The underlying mechanisms and the contribution of anaesthesia in particular to POCD remain unclear. Laboratory models suggest anaesthetic interactions with neurodegenerative mechanisms, such as those linked to the onset and progression of Alzheimer's disease, but their clinical relevance remains inconclusive. Prospective randomized clinical trials are underway to address the clinical significance of these findings, but there are major challenges in designing, executing, and interpreting such trials. It is unlikely that definitive clinical studies absolving general anaesthetics of neurotoxicity will become available in the near future, requiring clinicians to use careful judgement when using these profound neurodepressants in vulnerable patients.
doi:10.1093/bja/aer122
PMCID: PMC3159425  PMID: 21616941
anaesthesia, general; Alzheimer's disease; neurobehavioural manifestations; postoperative complications
3.  Sodium channels and the synaptic mechanisms of inhaled anaesthetics 
General anaesthetics act in an agent-specific manner on synaptic transmission in the central nervous system by enhancing inhibitory transmission and reducing excitatory transmission. The synaptic mechanisms of general anaesthetics involve both presynaptic effects on transmitter release and postsynaptic effects on receptor function. The halogenated volatile anaesthetics inhibit neuronal voltage-gated Na+ channels at clinical concentrations. Reductions in neurotransmitter release by volatile anaesthetics involve inhibition of presynaptic action potentials as a result of Na+ channel blockade. Although voltage-gated ion channels have been assumed to be insensitive to general anaesthetics, it is now evident that clinical concentrations of volatile anaesthetics inhibit Na+ channels in isolated rat nerve terminals and neurons, as well as heterologously expressed mammalian Na+ channel α subunits. Voltage-gated Na+ channels have emerged as promising targets for some of the effects of the inhaled anaesthetics. Knowledge of the synaptic mechanisms of general anaesthetics is essential for optimization of anaesthetic techniques for advanced surgical procedures and for the development of improved anaesthetics.
doi:10.1093/bja/aep144
PMCID: PMC2700013  PMID: 19508978
anaesthetics volatile; anaesthetics volatile, halogenated hydrocarbons; nerve, neurotransmitters; pharmacology, anaesthetic action; pharmacology, neurotransmission
4.  Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane 
BJA: British Journal of Anaesthesia  2009;102(3):355-360.
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.
doi:10.1093/bja/aen387
PMCID: PMC2642653  PMID: 19189985
anaesthetics volatile, isoflurane; brain, anaesthesia, molecular effects; brain, hippocampus; ions, ion channels, ligand-gated; nerve, neurotransmitters

Results 1-4 (4)