ReviewGABAA receptor subtypes underlying general anesthesia
Section snippets
Overview
Anesthetics have been used to relieve human suffering since the beginning of recorded time. Dioscorides (40–90 AD) first coined the Greek term “anesthesia” to describe an unnatural sleep caused by wine produced from the mandrake plant. Since then, general anesthesia has evolved into a sophisticated therapeutic intervention supported by state-of-the-art technology. Whereas the clinical use of anesthetics has mushroomed, an understanding of the mechanisms of drug action has lagged behind. Recent
Anesthetics and GABAA receptor physiology
GABA is the major inhibitory neurotransmitter in the mammalian brain, and as many as one-third of all synapses are GABAergic (Bloom and Iversen, 1971). Most inhibition is mediated by GABAA receptors, which are chloride-permeable ligand-gated ion channels. Activation of GABAA receptors generally leads to an influx of chloride, hyperpolarization of the membrane, shunting of excitatory input, and reduced excitability of the neurons. The GABAA receptor itself is a hetero-pentameric complex composed
Memory impairment by anesthetics and tonic inhibition
The impairment of memory is one of the most potent effects of many general anesthetics (Campagna et al., 2003), and the dose of etomidate that impairs memory is considerably lower than the dose that causes immobility (Cheng et al., 2006). From a clinical perspective, the disruption of memory by anesthetics has gained substantial attention from the medical and lay community. Amnesia is one of the most important effects of anesthetics, yet some patients experience inadequate amnesia during
Sedation and GABAA receptor isoforms
The terms sedation and hypnosis are sometimes used synonymously. However, here they are distinguished as recent studies suggest that different brain regions and receptor populations mediate sedation and hypnosis. Sedation in humans refers to a deceased level of arousal, as indicated by longer response times, decreased motor activity and slurred speech. In animal models, the surrogate measure for sedation is a reduction in motor activity and decreased arousal (Campagna et al., 2003). Hypnosis
Hypnosis and GABAA receptor isoforms
Hypnosis typically requires higher concentrations of anesthetics than sedation (Rudolph and Antkowiak, 2004) and is often measured by the loss of the righting reflex in rodents. Anesthetic action on GABAA receptors is implicated in hypnosis. The duration of the loss of righting reflex induced by etomidate was reduced in β2(Asn265Ser) mice (Reynolds et al., 2003; Fig. 3). Interestingly, the electroencephalographic patterns during etomidate anesthesia were similar for β2(Asn265Ser) and wild-type
Volatile anesthetics and GABAA receptor composition
Volatile anesthetics are low-potency compounds that influence a variety of receptors at clinically-relevant concentrations (Campagna et al., 2003). Thus, determining the specific sites of action that underlie the desirable therapeutic effects of volatile anesthetics is a challenge. In addition, behavioral testing with volatile anesthetics is difficult for practical reasons. Nevertheless, several carefully designed studies have suggested that several endpoints of isoflurane anesthesia are
Conclusions
Our knowledge of how general anesthetics act on their targets to produce anesthesia has advanced considerably over the past decade. Genetic manipulations and subunit-selective drugs have been used to identify discrete GABAA receptor populations that are key mediators of anesthesia endpoints such as sedation, hypnosis, and amnesia. Additionally, the discovery of endpoints specific for certain GABAA receptors is furthering our understanding of how these subunits contribute to the biology of
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