GABA anesthetics

AHopregnanolone and similar A-ring-reduced pregnanes potentiate GABA effects at these receptors. These steroids mimic the effects of the benzodiazepines, changing chloride ion conductance and producing sedative and hypnotic behavioral effects (276,277). Neuroactive steroids can be therapeutically useful as anticonvulsants, anxiolytics, or anesthetics (qv) (see also Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Severe withdrawal symptoms, including insomnia, irritability, agitation, withdrawal seizures, and delirium, have been described in both mice and humans chronically exposed to the anesthetics nitrous oxide, ether, and isoflurane (Arnold et al. 1993 Delteil et al. 1974 Deniker et al. 1972 Harper et al. 1980 Smith et al. 1979 Tobias 2000). These symptoms were controlled with the administration of y-aminobutyric acid (GABA)-ergic agents such as pentobarbital, midazolam, and diazepam (Arnold et al. 1993 Hughes et al. 1993). 

Most hypnotic drugs act on GABA receptors. It is reasonable to hypothesize that hypnotic actions are mediated by the GABA receptors on wake-promoting neurons innervated by POA sleep-active neurons, but there is little study of this problem. However, there is evidence that GABAergic anesthetics induce c-Fos IR in the VLPO and suppress c-Fos IR in histaminergic neurons (Nelson et al, 2002). 

GABA, and molecules that act at GABA-A receptors, have been classically recognized as hypnotics (i.e. benzodiazepines) and anesthetics (i.e. barbiturates). Benzodiazepine (BZD) receptors, a modulatory site on the GABA-A receptor, were... 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

The mechanisms of action of the effects of alcohol on the nervous system remain unclear. For some time, researchers thought that the depressant effects of alcohol, like other anesthetic agents, were caused by dissolving into the cell lipid membranes and disrupting the function of various proteins. More recently, researchers have focused on specific receptors such as glutamate (excitatory) and GABA (inhibitory). Despite intensive research, the mechanism of effect of alcohol on the fetus is unknown. 

No difference has been observed in the interactions of the two enantiomers of isoflurane with hpid bilayers. But the (5)-enantiomer of isoflurane is two times more active than the (7 )-enantiomer toward a calcium channel receptor, that is sensitive to volatile anesthetic agents, while nodifference in activity has been observed toward an anesthetic nonsensitive receptor. The (5)-enantiomer of isoflurane is also more active than the (R)-enantiomer toward acetylcholine nicotinic receptor and GABA receptor. These data strongly suggest that fluoroethers interact not only with cerebral membranous lipids but also with receptor proteins. 

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