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Moreover, increased susceptibility to stress has been proposed as an important factor for development, maintenance and relapse of cocaine addiction. As the glucocorticoid receptor gene (<jats:italic>NR3C1<\/jats:italic>) mediates genomic effects of the stress hormone cortisol, we investigated <jats:italic>NR3C1<\/jats:italic> expression and the association of <jats:italic>NR3C1<\/jats:italic> genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant\u2010na\u00efve healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood <jats:italic>NR3C1<\/jats:italic> mRNA levels were determined and six <jats:italic>NR3C1<\/jats:italic> polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower <jats:italic>NR3C1<\/jats:italic> expression (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), which was not affected by <jats:italic>NR3C1<\/jats:italic> genotypes. In controls, rs41423247 [<jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.01, false discovery rate (FDR)\u2010corrected], haplotype 2 and haplotype 3 (both <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, FDR\u2010corrected) were associated with altered <jats:italic>NR3C1<\/jats:italic> gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio\u00a0=\u00a02.74, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (<jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.01, FDR\u2010corrected) than noncarriers. Considering possible confounding effects of alcohol and\/or depression, we conclude that chronic cocaine use is associated with lower <jats:italic>NR3C1<\/jats:italic> gene expression suggesting possible direct effects of the drug on the biological adaptation of stress\u2010related genes. Finally, we postulate that haplotype 3 of <jats:italic>NR3C1<\/jats:italic> might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms.<\/jats:p>","DOI":"10.1111\/adb.12632","type":"journal-article","created":{"date-parts":[[2018,5,15]],"date-time":"2018-05-15T09:39:22Z","timestamp":1526377162000},"page":"730-742","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Glucocorticoid receptor gene variants and lower expression of <i>NR3C1<\/i> are associated with cocaine use"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9581-516X","authenticated-orcid":false,"given":"Andrea B.","family":"Schote","sequence":"first","affiliation":[{"name":"Department of Neurobehavioral Genetics, Institute of Psychobiology University of Trier  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"J\u00e4ger","sequence":"additional","affiliation":[{"name":"Department of Neurobehavioral Genetics, Institute of Psychobiology University of Trier  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9823-5171","authenticated-orcid":false,"given":"Sara L.","family":"Kroll","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital University of Zurich  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Vonmoos","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital University of Zurich  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lea M.","family":"Hulka","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital University of Zurich  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin H.","family":"Preller","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital University of Zurich  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jobst","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Neurobehavioral Genetics, Institute of Psychobiology University of Trier  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edna","family":"Gr\u00fcnblatt","sequence":"additional","affiliation":[{"name":"University Clinic for Child and Adolescent Psychiatry University of Zurich  Switzerland"},{"name":"NeuroscienceCenter Zurich University and ETH Zurich  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7933-2865","authenticated-orcid":false,"given":"Boris B.","family":"Quednow","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Pharmacopsychology, Department of Psychiatry, Psychotherapy, and Psychosomatics, Psychiatric Hospital University of Zurich  Switzerland"},{"name":"NeuroscienceCenter Zurich University and ETH Zurich  Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,5,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2282"},{"key":"e_1_2_8_3_1","volume-title":"Diagnostic and Statistical Manual of Mental Disorders DSM\u2010IV\u2010TR (Text Revision)","author":"American Psychiatric Association","year":"1999"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth457"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20103223(95)00083\u20106"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1961.01710120031004"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2015.05.002"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.2478\/s11536\u2010012\u20100101\u20101"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000072797"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1401660111"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000216192"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2007.11.072"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-11-04785.2003"},{"key":"e_1_2_8_14_1","volume-title":"SCL\u201090. 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