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A large body of data supports the concept that GABA<jats:sub>A<\/jats:sub>receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the \u03b23 GABA<jats:sub>A<\/jats:sub>\u2010receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent as a GABA<jats:sub>A<\/jats:sub>\u2010receptor modulator than pentobarbital, phenobarbital is minimally sedating at effective anticonvulsant doses. Possible explanations for the reduced sedative effect of phenobarbital include more regionally restricted action; partial agonist activity; reduced propensity to directly activate GABA<jats:sub>A<\/jats:sub>receptors (possibly including extrasynaptic receptors containing \u03b4 subunits); and reduced activity at other ion channel targets, including voltage\u2010gated calcium channels. In recent years, substantial progress has been made in defining the structural features of GABA<jats:sub>A<\/jats:sub>receptors responsible for gating and allosteric modulation by drugs. Although the precise sites of action of barbiturates have not yet been defined, the second and third transmembrane domains of the \u03b2 subunit appear to be critical; binding may involve a pocket formed by \u03b2\u2010subunit methionine 286 as well as \u03b1\u2010subunit methionine 236. In addition to effects on GABA<jats:sub>A<\/jats:sub>receptors, barbiturates block AMPA\/kainate receptors, and they inhibit glutamate release through an effect on P\/Q\u2010type high\u2010voltage activated calcium channels. The combination of these various actions likely accounts for their diverse clinical activities. Despite the remarkable progress of the last century, there is still much to learn about the actions of barbiturates that can be applied to the discovery of new, more therapeutically useful agents.<\/jats:p>","DOI":"10.1111\/epi.12025","type":"journal-article","created":{"date-parts":[[2012,12,4]],"date-time":"2012-12-04T07:39:06Z","timestamp":1354606746000},"page":"12-25","source":"Crossref","is-referenced-by-count":183,"title":["How theories evolved concerning the mechanism of action of barbiturates"],"prefix":"10.1111","volume":"53","author":[{"given":"Wolfgang","family":"L\u00f6scher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael 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