{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:05:15Z","timestamp":1782281115794,"version":"3.54.5"},"posted":{"date-parts":[[2026,1,21]]},"group-title":"Neuroscience","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"NIAAA","doi-asserted-by":"crossref","award":["R01AA026256"],"award-info":[{"award-number":["R01AA026256"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"crossref","award":["R25 HL007785"],"award-info":[{"award-number":["R25 HL007785"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000025","name":"NIMH","doi-asserted-by":"crossref","award":["R01 MH128235"],"award-info":[{"award-number":["R01 MH128235"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Alcohol use disorder is a major public health concern worldwide and there is a high comorbidity with psychiatric disorders. The basolateral amygdala (BLA) has been implicated in both mood and alcohol use disorders; however, the mechanisms contributing to the shared pathophysiology remain unknown. Extensive evidence indicates that ethanol modulates GABAergic signaling in the BLA, including actions on neurosteroid-sensitive, extrasynaptic \u03b4 subunit-containing GABA\n                  <jats:sub>A<\/jats:sub>\n                  receptors (GABA\n                  <jats:sub>A<\/jats:sub>\n                  Rs), which has been suggested to mediate many of the behavioral effects. In fact, several studies have suggested that 5\u03b1-reduced neurosteroids, such as allopregnanolone, may mediate some of the behavioral effects of alcohol. Here we demonstrate that chronic intermittent ethanol (CIE) exposure impairs endogenous neurosteroidogenesis via downregulation of key neurosteroidogenic enzymes, 5\u03b1-reductase type 1 and type 2. To examine the impact of impaired endogenous neurosteroidogenesis of the behavioral consequences of chronic alcohol exposure, including withdrawal-induced anxiety and increased alcohol consumption, we used CRISPR\/Cas9 mediated knockdown of 5\u03b1-reductase in the BLA. Reduced expression of 5\u03b1-reductase in the BLA did not impact post-CIE alcohol intake or anxiety-like behaviors during withdrawal, perhaps because endogenous neurosteroidogenesis is already impaired following CIE. Therefore, we examined the impact of enhancing neurosteroid levels, treating mice post-CIE with SGE-516, a synthetic GABA\n                  <jats:sub>A<\/jats:sub>\n                  R positive allosteric modulator, which increased voluntary alcohol intake. These findings implicate endogenous neurosteroidogenesis in behavioral outcomes associated with withdrawal from chronic alcohol exposure. Further, this study suggests that targeting endogenous neurosteroidogenesis may be a novel and useful therapeutic target.\n                <\/jats:p>","DOI":"10.64898\/2026.01.17.700089","type":"posted-content","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T02:20:10Z","timestamp":1769048410000},"source":"Crossref","is-referenced-by-count":0,"title":["Impact of impaired endogenous neurosteroidogenesis on outcomes following chronic alcohol exposure"],"prefix":"10.64898","author":[{"given":"Katrina","family":"Blandino","sequence":"first","affiliation":[{"name":"Neuroscience Program, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchu","family":"He","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifen","family":"Htet","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shadeh","family":"Okoudjou","sequence":"additional","affiliation":[{"name":"Building Diversity in Biomedical Sciences (BDBS) Program, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Lee","sequence":"additional","affiliation":[{"name":"Tufts University, Medford, MA, 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maia","family":"Chinatti","sequence":"additional","affiliation":[{"name":"Tufts University, Medford, MA, 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Ahn","sequence":"additional","affiliation":[{"name":"Tufts University, Medford, MA, 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Lewis","sequence":"additional","affiliation":[{"name":"SAGE Therapeutics, Inc., Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gray","sequence":"additional","affiliation":[{"name":"SAGE Therapeutics, Inc., Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Miczek","sequence":"additional","affiliation":[{"name":"Tufts University, Medford, MA, 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Maguire","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020608081016000_2026.01.17.700089v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2014.02.032"},{"key":"2026020608081016000_2026.01.17.700089v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2021.07.017"},{"key":"2026020608081016000_2026.01.17.700089v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01266-1"},{"key":"2026020608081016000_2026.01.17.700089v1.4","doi-asserted-by":"publisher","DOI":"10.1097\/01.ALC.0000149977.95306.3A"},{"key":"2026020608081016000_2026.01.17.700089v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1971.tb07157.x"},{"key":"2026020608081016000_2026.01.17.700089v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/0-306-47138-8_16"},{"key":"2026020608081016000_2026.01.17.700089v1.7","doi-asserted-by":"publisher","DOI":"10.1037\/h0077898"},{"key":"2026020608081016000_2026.01.17.700089v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2021.108912"},{"key":"2026020608081016000_2026.01.17.700089v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-44286-0"},{"key":"2026020608081016000_2026.01.17.700089v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301150"},{"key":"2026020608081016000_2026.01.17.700089v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-020-05589-7"},{"key":"2026020608081016000_2026.01.17.700089v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/jne.12996"},{"key":"2026020608081016000_2026.01.17.700089v1.13","doi-asserted-by":"publisher","DOI":"10.1111\/jne.13378"},{"key":"2026020608081016000_2026.01.17.700089v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2022.09.143"},{"key":"2026020608081016000_2026.01.17.700089v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.yhbeh.2009.07.002"},{"key":"2026020608081016000_2026.01.17.700089v1.16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2008.00718.x"},{"key":"2026020608081016000_2026.01.17.700089v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.01.026"},{"key":"2026020608081016000_2026.01.17.700089v1.18","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph20206939"},{"key":"2026020608081016000_2026.01.17.700089v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108299"},{"key":"2026020608081016000_2026.01.17.700089v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.addicn.2022.100035"},{"key":"2026020608081016000_2026.01.17.700089v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2016.01.023"},{"key":"2026020608081016000_2026.01.17.700089v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2016.08.006"},{"key":"2026020608081016000_2026.01.17.700089v1.23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.1998.tb03708.x"},{"key":"2026020608081016000_2026.01.17.700089v1.24","doi-asserted-by":"publisher","DOI":"10.1159\/000508681"},{"key":"2026020608081016000_2026.01.17.700089v1.25","doi-asserted-by":"publisher","DOI":"10.3109\/15622970209150606"},{"key":"2026020608081016000_2026.01.17.700089v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2004.11.001"},{"key":"2026020608081016000_2026.01.17.700089v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.04.050"},{"key":"2026020608081016000_2026.01.17.700089v1.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-012-2770-5"},{"key":"2026020608081016000_2026.01.17.700089v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-15617-5"},{"key":"2026020608081016000_2026.01.17.700089v1.30","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2016.00206"},{"key":"2026020608081016000_2026.01.17.700089v1.31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2002.tb02479.x"},{"issue":"10152","key":"2026020608081016000_2026.01.17.700089v1.32","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0140-6736(18)31551-4","article-title":"Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials","volume":"392","year":"2018","journal-title":"The Lancet"},{"key":"2026020608081016000_2026.01.17.700089v1.33","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2006.8.4\/amorrow"},{"key":"2026020608081016000_2026.01.17.700089v1.34","doi-asserted-by":"publisher","DOI":"10.1111\/acer.14253"},{"key":"2026020608081016000_2026.01.17.700089v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/bs.irn.2024.07.004"},{"key":"2026020608081016000_2026.01.17.700089v1.36","doi-asserted-by":"publisher","DOI":"10.1111\/acer.14901"},{"key":"2026020608081016000_2026.01.17.700089v1.37","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2022.907552"},{"key":"2026020608081016000_2026.01.17.700089v1.38","doi-asserted-by":"publisher","DOI":"10.1111\/acer.15008"},{"key":"2026020608081016000_2026.01.17.700089v1.39","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.24203"},{"key":"2026020608081016000_2026.01.17.700089v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2020.100215"},{"key":"2026020608081016000_2026.01.17.700089v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2015.01.004"},{"key":"2026020608081016000_2026.01.17.700089v1.42","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0234-24.2024"},{"key":"2026020608081016000_2026.01.17.700089v1.43","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph20075301"},{"key":"2026020608081016000_2026.01.17.700089v1.44","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-019-05335-8"},{"key":"2026020608081016000_2026.01.17.700089v1.45","doi-asserted-by":"publisher","DOI":"10.1111\/acer.13444"},{"key":"2026020608081016000_2026.01.17.700089v1.46","doi-asserted-by":"publisher","DOI":"10.3109\/15622970009150572"},{"key":"2026020608081016000_2026.01.17.700089v1.47","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-014-3558-6"},{"key":"2026020608081016000_2026.01.17.700089v1.48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0075-04.2004"},{"key":"2026020608081016000_2026.01.17.700089v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2021.109065"},{"key":"2026020608081016000_2026.01.17.700089v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2017.161"},{"key":"2026020608081016000_2026.01.17.700089v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.alcohol.2023.05.004"},{"key":"2026020608081016000_2026.01.17.700089v1.52","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-025-00701-y"},{"key":"2026020608081016000_2026.01.17.700089v1.53","doi-asserted-by":"publisher","DOI":"10.1111\/dar.13143"},{"key":"2026020608081016000_2026.01.17.700089v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2024.06.011"},{"key":"2026020608081016000_2026.01.17.700089v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2014.11.006"},{"key":"2026020608081016000_2026.01.17.700089v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300170"},{"key":"2026020608081016000_2026.01.17.700089v1.57","doi-asserted-by":"crossref","first-page":"110833","DOI":"10.1016\/j.neuropharm.2026.110833","article-title":"Assessing the utility of the neurosteroid zuranolone to modify alcohol-related behaviours","volume":"288","year":"2026","journal-title":"Neuropharmacology"},{"key":"2026020608081016000_2026.01.17.700089v1.58","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-05-01982.2000"},{"key":"2026020608081016000_2026.01.17.700089v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(02)00126-0"},{"key":"2026020608081016000_2026.01.17.700089v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2023.01.022"},{"key":"2026020608081016000_2026.01.17.700089v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2013.261"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.17.700089","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:16:12Z","timestamp":1782278172000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.17.700089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":61,"URL":"https:\/\/doi.org\/10.64898\/2026.01.17.700089","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.alcohol.2026.04.008","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2026,1,21]]},"subtype":"preprint"}}