RGD Reference Report - Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use. - Rat Genome Database

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Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use.

Authors: Schote, Andrea B  Jäger, Kristina  Kroll, Sara L  Vonmoos, Matthias  Hulka, Lea M  Preller, Katrin H  Meyer, Jobst  Grünblatt, Edna  Quednow, Boris B 
Citation: Schote AB, etal., Addict Biol. 2019 Jul;24(4):730-742. doi: 10.1111/adb.12632. Epub 2018 May 15.
RGD ID: 407987269
Pubmed: PMID:29761890   (View Abstract at PubMed)
DOI: DOI:10.1111/adb.12632   (Journal Full-text)

Animal and cross-sectional human studies suggest that chronic cocaine use is associated with altered responsivity of the hypothalamic-pituitary-adrenal axis to stress. 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 (NR3C1) mediates genomic effects of the stress hormone cortisol, we investigated NR3C1 expression and the association of NR3C1 genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant-naïve healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood NR3C1 mRNA levels were determined and six NR3C1 polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower NR3C1 expression (P < 0.001), which was not affected by NR3C1 genotypes. In controls, rs41423247 [P < 0.01, false discovery rate (FDR)-corrected], haplotype 2 and haplotype 3 (both P < 0.05, FDR-corrected) were associated with altered NR3C1 gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio = 2.74, P < 0.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (P < 0.01, FDR-corrected) than noncarriers. Considering possible confounding effects of alcohol and/or depression, we conclude that chronic cocaine use is associated with lower NR3C1 gene expression suggesting possible direct effects of the drug on the biological adaptation of stress-related genes. Finally, we postulate that haplotype 3 of NR3C1 might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
NR3C1Humancocaine abuse  IEP mRNA:decreased expression:bloodRGD 
Nr3c1Ratcocaine abuse  ISONR3C1 (Homo sapiens)mRNA:decreased expression:bloodRGD 
Nr3c1Mousecocaine abuse  ISONR3C1 (Homo sapiens)mRNA:decreased expression:bloodRGD 

Objects Annotated

Genes (Rattus norvegicus)
Nr3c1  (nuclear receptor subfamily 3, group C, member 1)

Genes (Mus musculus)
Nr3c1  (nuclear receptor subfamily 3, group C, member 1)

Genes (Homo sapiens)
NR3C1  (nuclear receptor subfamily 3 group C member 1)


Additional Information