{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T08:39:21Z","timestamp":1769503161692,"version":"3.49.0"},"reference-count":65,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,1,9]],"date-time":"2017-01-09T00:00:00Z","timestamp":1483920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006808","name":"University of North Carolina","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006808","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Alcoholism Clin &amp;amp; Exp Res"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The GABAergic neuroactive steroid (3\u03b1,5\u03b1)\u20103\u2010hydroxy\u2010pregnan\u201020\u2010one (3\u03b1,5\u03b1\u2010THP; allopregnanolone) enhances GABAergic activity and produces subjective effects similar to ethanol (EtOH). The effect of chronic alcohol exposure on 3\u03b1,5\u03b1\u2010THP concentrations has been studied in mouse, rat, and monkey limbic brain areas. Chronic EtOH exposure produced divergent brain region and cell\u2010specific changes in 3\u03b1,5\u03b1\u2010THP concentrations in animal studies. However,\u00a03\u03b1,5\u03b1\u2010THP levels in similar human brain regions have never been examined in individuals diagnosed with alcohol use disorder (AUD). Therefore, we used immunohistochemistry (IHC) to examine 3\u03b1,5\u03b1\u2010THP levels in the ventral tegmental area (VTA), substantia nigra pars medialis (SNM), and amygdala of human postmortem brains of patients diagnosed with AUD compared with social drinkers. The effects of sex and liver disease on 3\u03b1,5\u03b1\u2010THP concentrations were examined in the aforementioned brain regions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human postmortem brains of AUD patients and age\u2010matched controls were obtained from the New South Wales Brain Tissue Resource Center. IHC was performed using anti\u20103\u03b1,5\u03b1\u2010THP antibody on formalin\u2010fixed paraffin\u2010embedded brain sections to detect cellular 3\u03b1,5\u03b1\u2010THP levels. Immunoreactivity was analyzed by pixel density\/mm<jats:sup>2<\/jats:sup>for the comparison between AUD patients and controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>3\u03b1,5\u03b1\u2010THP immunoreactivity was increased by 23.2\u00a0\u00b1\u00a09% in the VTA of AUD patients compared with age\u2010matched controls (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.014). Moreover, a 29.6\u00a0\u00b1\u00a010% increase in 3\u03b1,5\u03b1\u2010THP immunoreactivity was observed in the SNM of male AUD patients compared with male controls (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.01), but not in female subjects. 3\u03b1,5\u03b1\u2010THP immunoreactivity in the VTA and SNM regions did not differ between noncirrhotic and cirrhotic AUD patients. A sex difference in 3\u03b1,5\u03b1\u2010THP immunoreactivity (female 51\u00a0\u00b1\u00a018% greater than male) was observed among control subjects in the SNM, but no other brain region. 3\u03b1,5\u03b1\u2010THP immunoreactivity in the basolateral amygdala and lateral amygdala was negatively correlated with the length of the tissue fixation time as well as the age of the subjects, precluding assessment of the effect of AUD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Cellular 3\u03b1,5\u03b1\u2010THP levels in VTA are increased in human AUD patients, an effect that is likely independent of sex and liver disease. The differences between animal models and human studies should be factored into the interpretation of the physiological significance of elevated 3\u03b1,5\u03b1\u2010THP levels in humans.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13300","type":"journal-article","created":{"date-parts":[[2017,1,9]],"date-time":"2017-01-09T19:25:13Z","timestamp":1483989913000},"page":"299-311","source":"Crossref","is-referenced-by-count":19,"title":["Cellular GABAergic Neuroactive Steroid (3\u03b1,5\u03b1)\u20103\u2010Hydroxy\u2010Pregnan\u201020\u2010One (3\u03b1,5\u03b1\u2010THP) Immunostaining Levels Are Increased in the Ventral Tegmental Area of Human Alcohol Use Disorder Patients: A Postmortem Study"],"prefix":"10.1111","volume":"41","author":[{"given":"Ahmet Sait","family":"Hasirci","sequence":"first","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoniette M.","family":"Maldonado\u2010Devincci","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C.","family":"Beattie","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8723-734X","authenticated-orcid":false,"given":"Todd K.","family":"O'Buckley","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Leslie","family":"Morrow","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies University of North Carolina at Chapel Hill Chapel Hill North Carolina"},{"name":"Department of Psychiatry University of North Carolina at Chapel Hill Chapel Hill North Carolina"},{"name":"Department of Pharmacology University of North Carolina at Chapel Hill Chapel Hill North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,1,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2007.01080.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2006.02.002"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4173-05.2005"},{"key":"e_1_2_8_5_1","volume-title":"Diagnostic and Statistical Manual\u00a0of Mental Disorders","author":"American Psychiatric 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