title: Effects of the circadian rhythm gene period 1 (per1) on psychosocial stress-induced alcohol drinking.
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.
  
  
  METHODS
  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.
authors.affiliation: Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Dong
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.forename: Manfred
authors.initials: M
authors.lastname: Laucht
authors.forename: Richard
authors.initials: R
authors.lastname: Henriksson
authors.forename: Tatjana
authors.initials: T
authors.lastname: Yakovleva
authors.forename: Monika
authors.initials: M
authors.lastname: Ridinger
authors.forename: Sylvane
authors.initials: S
authors.lastname: Desrivieres
authors.forename: Toni-Kim
authors.initials: TK
authors.lastname: Clarke
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Dorothea
authors.initials: D
authors.lastname: Blomeyer
authors.forename: Jens
authors.initials: J
authors.lastname: Treutlein
authors.forename: Stephanie
authors.initials: S
authors.lastname: Perreau-Lenz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Witt
authors.forename: Fernando
authors.initials: F
authors.lastname: Leonardi-Essmann
authors.forename: Norbert
authors.initials: N
authors.lastname: Wodarz
authors.forename: Peter
authors.initials: P
authors.lastname: Zill
authors.forename: Michael
authors.initials: M
authors.lastname: Soyka
authors.forename: Urs
authors.initials: U
authors.lastname: Albrecht
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.forename: Gunter
authors.initials: G
authors.lastname: Schumann
mesh_terms: D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology; D000483:Alleles; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics*
chemical_list: C539022:PER1 protein, human; D056950:Period Circadian Proteins