Citation

Dong L, Bilbao A, Laucht M, Henriksson R, Yakovleva T, Ridinger M, Desrivieres S, Clarke TK, Lourdusamy A, Smolka MN, Cichon S, Blomeyer D, Treutlein J, Perreau-Lenz S, Witt S, Leonardi-Essmann F, Wodarz N, Zill P, Soyka M, Albrecht U, Rietschel M, Lathrop M, Bakalkin G, Spanagel R, Schumann G. Am. J. Psychiatry 2011; 168(10): 1090-1098.

Affiliation

Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London; the Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany; the Uppsala Biomedical Centre, Uppsalla, Sweden; the Department of Psychiatry and Psychotherapy, University of Regensburg-Bezirksklinikum, Regensburg, Germany; the Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany; the Neuroimaging Center, Department of Psychology, Technische Universität Dresden, Dresden, Germany; the Department of Genomics, Life and Brain Centre, University of Bonn, Bonn, Germany; the Department of Psychiatry and Psychotherapy, University of Munich, Munich; the Department of Medicine, Unit of Biochemistry, University of Fribourg, Fribourg, Switzerland; and the Centre National de Genotypage, Evry, France.

Copyright

(Copyright © 2011, American Psychiatric Association)

DOI

10.1176/appi.ajp.2011.10111579

PMID

21828288

Abstract

Objective: Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1 (Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor-expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking. Method: In mice, the effects of stress on ethanol intake in mPer1-mutant and wild-type mice were assessed. In humans, single nucleotide polymorphisms (SNPs) in hPer1 were tested for association with alcohol drinking behavior in 273 adolescents and an adult case-control sample of 1,006 alcohol-dependent patients and 1,178 comparison subjects. In vitro experiments were conducted to measure genotype-specific expression and transcription factor binding to hPer1. Results: The mPer1-mutant mice showed enhanced alcohol consumption in response to social defeat stress relative to their wild-type littermates. An association with the frequency of heavy drinking in adolescents with the hPer1 promoter SNP rs3027172 and with psychosocial adversity was found. There was significant interaction between the rs3027172 genotype and psychosocial adversity on this drinking measure. In a confirmatory analysis, association of hPer1 rs3027172 with alcohol dependence was shown. Cortisol-induced transcriptional activation of hPer1 was reduced in human B-lymphoblastoid cells carrying the risk genotype of rs3027172. Binding affinity of the transcription factor Snail1 to the risk allele of the hPer1 SNP rs3027172 was also reduced. Conclusions: The findings indicate that the hPer1 gene regulates alcohol drinking behavior during stressful conditions and provide evidence for underlying neurobiological mechanisms.

Language: en