TY  - JOUR
T1  - CRh haplotype as a factor influencing cerebrospinal fluid levels of corticotropin-releasing hormone, hypothalamic-pituitary-adrenal axis activity, temperament, and alcohol consumption in rhesus macaques
AU  - Barr CS, Dvoskin RL, Yuan Q, et al
Y1  - 2008/08/04
N1  - 10.1001/archpsyc.65.8.934
JO  - Archives of General Psychiatry
SP  - 934
EP  - 944
VL  - 65
IS  - 8
N2  - Context 
    Both highly stress-reactive and novelty-seeking individuals are susceptible to alcohol use disorders. Variation in stress reactivity, exploration, and response to novelty have been attributed to differences in corticotropin-releasing hormone (CRH) system function. As such, CRH gene variation may influence risk for alcohol use and dependence.Objective 
    To determine whether CRH variation influences relevant intermediate phenotypes, behavior, and alcohol consumption in rhesus macaques.Design 
    We sequenced the rhesus macaque CRH locus (rhCRH) and performed cladistic clustering of haplotypes. In silico analysis, gel shift, and in vitro reporter assays were performed to identify functional variants. Cerebrospinal fluid (CSF) and blood samples were obtained, and levels of CRH and corticotropin (ACTH) were measured by radioimmunoassay. Behavioral data were collected from macaques during infancy. Among adolescent/adult animals, we recorded responses to an unfamiliar conspecific and measured levels of ethanol consumption.Setting 
    National Institutes of Health Animal Center.Participants 
    Rhesus macaques.Main Outcome Measures 
    Animals were genotyped for a single-nucleotide polymorphism disrupting a glucocorticoid response element, rhCRH −2232 C>G, and the effects of this allele on CSF levels of CRH, plasma levels of ACTH, behavior, and ethanol consumption were assessed by analysis of variance.Results 
    We show that −2232C>G alters DNA×protein interactions and confers decreased sensitivity of the CRH promoter to glucocorticoids in vitro. Consistent with the known effects of glucocorticoids on CRH expression in the brain, carriers of the G allele had lower CSF levels of CRH but higher levels of ACTH. Infants carrying the G allele were more exploratory and bold, and among adolescent and adult male macaques, the G allele was associated with exploratory/bold responding to an unfamiliar male. Adults with the C/G genotype also exhibited increased alcohol consumption in the social group, a model for high-risk alcohol-seeking behavior.Conclusion 
    Haplotypes that differ in terms of corticosteroid sensitivity have been identified in humans. Our data may suggest that functionally similar CRH variants could influence risk for externalizing disorders in human subjects.
SN  - 0003-990X
M3  - doi: 10.1001/archpsyc.65.8.934
UR  - http://dx.doi.org/10.1001/archpsyc.65.8.934
ER  -