{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T01:05:18Z","timestamp":1791939918866,"version":"4.3.4"},"reference-count":45,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Applied Physiology"],"published-print":{"date-parts":[[2012,10,1]]},"abstract":"<jats:p>Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive\/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g\/kg ip). Pentobarbital induced an \u223c50% reduction in respiratory frequency in vitro (50 \u03bcM) and in vivo (28 mg\/kg for pups and 56 mg\/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABA<jats:sub>A<\/jats:sub>receptors, which was exacerbated by hypoxic (8% O<jats:sub>2<\/jats:sub>) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50\u2013150 \u03bcM) and in vivo (30 mg\/kg ip). Bicuculline also alleviated ethanol-\/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.<\/jats:p>","DOI":"10.1152\/japplphysiol.00752.2012","type":"journal-article","created":{"date-parts":[[2012,7,28]],"date-time":"2012-07-28T10:45:05Z","timestamp":1343472305000},"page":"1004-1011","source":"Crossref","is-referenced-by-count":43,"title":["Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717"],"prefix":"10.1152","volume":"113","author":[{"given":"Jun","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqing","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Greer","sequence":"additional","affiliation":[{"name":"Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","volume-title":"American Association for Geriatric Psychiatry (AAGP) 2010 Annual Meeting: Abs NR5","author":"Abrams RC"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2003.10.033"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-7368(67)70369-2"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1998.00396.x"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(95)00903-4"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.7.1.1"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2004.02.004"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703039"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1993.70.4.1497"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1979.tb01648.x"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1991.sp018622"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1992.67.4.996"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2170\/jjphysiol.50.15"},{"key":"B14","first-page":"395","volume-title":"Handbook of Drug Interactions: A Clinical and Forensic Guide","author":"Jones AW","year":"2003"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1990.64.2.423"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008766"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2005.09.005"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.1995.tb01617.x"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1990.69.4.1296"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1139\/y99-001"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.194"},{"key":"B22","unstructured":"Olin BR , Hebel SK , Dewein AC (editors).Drug Facts and Comparisons. 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