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This process in turn leads to <jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> influx upon activation of \u03b3\u2010aminobutyric acid type <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content>) receptors and the canonical hyperpolarising inhibitory postsynaptic potential. Several neurological disorders are treated with drugs that target and enhance <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> receptor signaling, including the commonly used benzodiazepine diazepam and the anesthetic propofol. Some of these disorders are also associated with deficits in <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> signaling and become less sensitive to therapeutic drugs that target <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> receptors. To date, it is unknown if alterations in the neuronal <jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> gradient affect the efficacies of diazepam and propofol. We therefore used the <jats:italic>in vitro<\/jats:italic> model of glutamate\u2010induced hyperexcitability to test if alterations in the <jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> gradient affect the efficacy of <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> modulators. We exclusively utilised the gramicidin perforated\u2010patch\u2010clamp configuration to preserve the endogenous <jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> gradient in rat neurons. Brief exposure to glutamate reduced the inhibitory efficacy of diazepam within 5\u00a0min, which was caused by the collapse of the <jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> gradient, and not due to reductions in <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content> receptor number. Unlike diazepam, propofol retained its efficacy by shunting the membrane conductance despite the glutamate\u2010induced appearance of depolarising <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content>\u2010mediated currents. Similarly, pharmacological inhibition of <jats:styled-content style=\"fixed-case\">K<\/jats:styled-content><jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> cotransporter type 2 by furosemide disrupted <jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> homeostasis and reduced the efficacy of diazepam but not propofol. Collectively our results suggest that pathological hyperexcitable conditions could cause the rapid accumulation of intracellular <jats:styled-content style=\"fixed-case\">Cl<\/jats:styled-content><jats:sup>\u2212<\/jats:sup> and the appearance of depolarising <jats:styled-content style=\"fixed-case\">GABA<jats:sub>A<\/jats:sub><\/jats:styled-content>\u2010mediated currents that would decrease the efficacy of diazepam.<\/jats:p>","DOI":"10.1111\/ejn.12241","type":"journal-article","created":{"date-parts":[[2013,4,30]],"date-time":"2013-04-30T02:57:04Z","timestamp":1367290624000},"page":"2453-2467","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Disrupted Cl<sup>\u2212<\/sup> homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states"],"prefix":"10.1111","volume":"38","author":[{"given":"Tarek Z.","family":"Deeb","sequence":"first","affiliation":[{"name":"Department of Neuroscience Tufts University Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuko","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Tufts University Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greg D.","family":"Frost","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Tufts University Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul A.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Tufts University Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J.","family":"Moss","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Tufts University Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,4,29]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.4.814"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.65.1.68"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.04.023"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.03.003"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/2661"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09511"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01868"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.4161\/chan.5.6.17952"},{"key":"e_1_2_6_10_1","doi-asserted-by":"crossref","first-page":"8069","DOI":"10.1523\/JNEUROSCI.20-21-08069.2000","article-title":"Potassium\u2010coupled chloride cotransport controls intracellular chloride in rat neocortical pyramidal neurons","volume":"20","author":"DeFazio R.A.","year":"2000","journal-title":"J. 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