Etomidate stereospecifically stimulates forebrain, but not cerebellar, 3H-diazepam binding

Distinct Loci Mediate the Direct and Indirect Actions of the Anesthetic Etomidate at GABAA Receptors

“…Pharmacologically relevant concentrations of intravenous anesthetics (e.g., barbiturates, etomidate, alphaxalone, propofol) produce multiple actions at GABAA receptors (Ashton et al, 1981;Schwartz et al, 1985;Moody et al, 1988;Lin et al, 1992). Although previous studies have demonstrated that a /3 subunit is required for the GABA-positive actions of a range of structurally unrelated intravenous agents in recombinant receptors composed of a 1/32/3 y2 subunits (Harris et a!., 1995), this report identifies a specific amino acid necessary for action of etomidate at this receptor.…”

“…This effect, often referred to as an "indirect action," is also characteristic of other drugs with sedative/hypnotic properties [e.g., diazepam (Sigel et al, 1990) and phenobarbital (Schulz andMacDonald, 1981)1 that are by themselves not efficacious anesthetic agents. At higher concentrations, intravenous anesthetics have a direct action, increasing chloride conductance in the nominal absence of GABA (Study and Barker, 1981;Sigel et al, 1990), suggesting that this direct effect may be related to the process of anesthesia.There are often marked differences among brain regions in the action of anesthetics at GABAA receptors (Ashton et al, 1981;Harris et al, 1993), and such differences are likely to reflect the regional heterogeneity of GABAA receptors (Wisden et al, 1992). This hypothesis is consistent with studies in recombinant GABAA receptors demonstrating that subunit composition has a dramatic effect on drug action (Sigel et al, 1990;Luddens et al, 1994).…”

“…There are often marked differences among brain regions in the action of anesthetics at GABAA receptors (Ashton et al, 1981;Harris et al, 1993), and such differences are likely to reflect the regional heterogeneity of GABAA receptors (Wisden et al, 1992). This hypothesis is consistent with studies in recombinant GABAA receptors demonstrating that subunit composition has a dramatic effect on drug action (Sigel et al, 1990;Luddens et al, 1994).…”

Binding of3H-DMCM to benzodiazepine receptors; chloride dependent allosteric regulation mechanisms

“…The hypnotic and anticonvulsant agent etomidate regulates benzodiazepine binding probably via interaction with the chloride ionophore (Ashton et al, 1981;Ehlert et aL, 1982;Thyagarajan et aL, 1983). Similarly, etomidate regulates the binding of 3H-DMCM at 37 ~ (Table 2).…”

“…The coupling of the BZ/GABA receptor complex to chloride ionophors is indicated by the finding that the affinity of BZ receptors for benzodiazepines is increased in the presence of chloride and certain other anions that penetrate chloride ionophors Martin and Candy, 1980). Furthermore, etomidate, some barbiturates and pyrazolopyridazines, which are believed to interact directly with chloride ionophors, enhance the binding of 3H-diazepam and 3H-flunitrazepam to BZ receptors (Ashton et aL, 1981;Leeb-Lundberg and Olsen, 1982;Ticku, 1981;Skolnick et al, 1982;Supavilai and Karobath, 1979). Likewise, the binding of 3H-GABA to GABA receptors is enhanced by etomidate, barbiturates and pyrazolopyridazines (Thyagarajan et al, 1983;Willow and Johnston, 1981;Willow, 1981;Placheta and Karobath, 1980).…”