{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T23:22:50Z","timestamp":1779232970329,"version":"3.51.4"},"reference-count":63,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,12,14]],"date-time":"2015-12-14T00:00:00Z","timestamp":1450051200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,1,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In premature newborns, recurrent apnoea is systematically treated with caffeine to prevent long\u2010term neurocognitive disorders, but a substantial percentage of apnoea persists particularly in neonates born before 28 weeks of gestation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Progesterone has been proposed as a respiratory stimulant potentially suitable for the treatment of newborn apnoea persistent to caffeine. Accordingly we asked whether acute progesterone administration reduces apnoea frequency in newborn rats treated with caffeine.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Surprisingly our results show that in newborn rats treated with caffeine, administration of progesterone inhibits breathing and increases apnoea frequency.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Additional experiments showed an enhanced GABAergic inhibitory drive on breathing after caffeine treatment, and that progesterone is converted to allopregnanolone (an allosteric modulator of GABA<jats:sub>A<\/jats:sub> receptors) to inhibit breathing.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conclude that combining progesterone and chronic caffeine is not an option in preterm neonates, unless the effects of allopregnanolone can be counteracted.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Caffeine is the main treatment for apnoea in preterm neonates, but its interactions with other respiratory stimulants like progesterone are unknown. We tested the hypothesis that the addition of progesterone to caffeine treatments further stimulates ventilation. Newborn rats were treated with water (control) or caffeine (15\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>) by daily gavage between postnatal day (P)3 and P12. At P4 and P12, we measured apnoea frequency, ventilatory responses and metabolic parameters under both normoxia and hypoxia (12% O<jats:sub>2<\/jats:sub>, 20\u00a0min) following an acute administration of either saline or progesterone (4\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>; <jats:sc>i.p.<\/jats:sc>). Progesterone injection increased the serum levels of both progesterone and its neuroactive metabolite allopregnanolone. Progesterone had no effect on ventilation in control rats under normoxia. Progesterone depressed ventilation in P12 caffeine\u2010treated rats under normoxia and hypoxia and increased apnoea frequency in both P4 and P12 rats. Because allopregnanolone is an allosteric modulator of GABA<jats:sub>A<\/jats:sub> receptors and caffeine may enhance GABAergic inhibition in newborns, we studied the effects of the GABA<jats:sub>A<\/jats:sub> receptor antagonist bicuculline at 0, 1, 2 and 3\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup> doses and allopregnanolone (10\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup> dose) in P12 rats. In caffeine\u2010treated rats, bicuculline enhanced ventilation, while allopregnanolone decreased ventilation and increased total apnoea time. Progesterone had no effect on ventilation and apnoea frequency in caffeine\u2010treated rats injected with finasteride, which blocks the conversion of progesterone to allopregnanolone. We conclude that combining progesterone and chronic caffeine therapy is not an option for the treatment of persistent apnoea in preterm neonates, unless the effects of allopregnanolone can be counteracted.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp270914","type":"journal-article","created":{"date-parts":[[2015,10,24]],"date-time":"2015-10-24T04:21:19Z","timestamp":1445660479000},"page":"373-389","source":"Crossref","is-referenced-by-count":13,"title":["Inhibitory respiratory responses to progesterone and allopregnanolone in newborn rats chronically treated with caffeine"],"prefix":"10.1113","volume":"594","author":[{"given":"NagaPraveena","family":"Uppari","sequence":"first","affiliation":[{"name":"Unit\u00e9 de recherche en p\u00e9rinatologie, Centre Hospitalier Universitaire de Qu\u00e9bec, H\u00f4pital Saint\u2010Fran\u00e7ois d'Assise, D\u00e9partement de P\u00e9diatrie Universit\u00e9 Laval  Qu\u00e9bec QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Joseph","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de recherche en p\u00e9rinatologie, Centre Hospitalier Universitaire de Qu\u00e9bec, H\u00f4pital Saint\u2010Fran\u00e7ois d'Assise, D\u00e9partement de P\u00e9diatrie Universit\u00e9 Laval  Qu\u00e9bec QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aida","family":"Bairam","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de recherche en p\u00e9rinatologie, Centre Hospitalier Universitaire de Qu\u00e9bec, H\u00f4pital Saint\u2010Fran\u00e7ois d'Assise, D\u00e9partement de P\u00e9diatrie Universit\u00e9 Laval  Qu\u00e9bec QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,12,14]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(87)80569-3"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2012.11.001"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2012.06.016"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-18440-1_23"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(70)90056-3"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2008.06.006"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.08.005"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00809.2002"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-3057(00)00237-9"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2013.00108"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2006.10.004"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2014.05.015"},{"key":"e_1_2_5_14_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1542\/peds.16.1.81","article-title":"A barometric method for measuring ventilation in newborn infants","volume":"16","author":"Drorbough JE","year":"1955","journal-title":"Pediatrics"},{"key":"e_1_2_5_15_1","first-page":"317","article-title":"Peripheral mechanisms of thermogenesis induced by ephedrine and caffeine in brown adipose tissue","volume":"15","author":"Dulloo AG","year":"1991","journal-title":"Int J Obes"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2009.05.013"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021330"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2005-0620H"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199707000-00008"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-4584-1_6"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2012.11.002"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00195.2013"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00884.2007"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2011.05.006"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-6576.2005.00896.x"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2006.08.007"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2010.11.026"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0922-4106(89)90028-X"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2007.01.005"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0301-0082(92)90025-A"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2422758"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c100021"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00459.2005"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.07.006"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000203105.63246.8a"},{"key":"e_1_2_5_37_1","first-page":"693","article-title":"[Effect of etimizol, caffeine and theophylline on some carbohydrate metabolic indices of the rat brain and myocardium]","volume":"38","author":"Moreva EV","year":"1975","journal-title":"Farmakol Toksikol"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00484.2014"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2009.049312"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/207426"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.07.026"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2013.09.009"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2004.09.002"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(99)01399-5"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201410-1898OC"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0026-06.2006"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.108829"},{"key":"e_1_2_5_48_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1152\/jappl.1986.61.1.255","article-title":"Ventilatory effect of an adenosine analogue in unanaesthetized rabbits during development","volume":"61","author":"Runold M","year":"1986","journal-title":"J Appl Physiol"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.09.004"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200210-1238OC"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1006901005925"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00733753"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(87)90634-2"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2011.12.011"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2004.04.012"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2005.01.011"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2008.04.014"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2012.05.026"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-3623(86)90203-X"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(92)90373-A"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/734367"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.165035"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-011-1409-6"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2009.07.001"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP270914","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP270914","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T22:58:45Z","timestamp":1696201125000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP270914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,14]]},"references-count":63,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,1,15]]}},"alternative-id":["10.1113\/JP270914"],"URL":"https:\/\/doi.org\/10.1113\/jp270914","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,14]]}}}