Functional CRH variation increases stress-induced alcohol consumption in primates.
Corticotropin-releasing factor (CRF), encoded by the CRH gene, is a key integrator of stress responses, and, as such, CRH gene variation may contribute to individual differences in susceptibility to stress-related pathology. In rhesus macaques, a single nucleotide polymorphism (SNP) is found within the CRH promoter (-248C--> T). Here, we assessed whether this variant influenced stress responding and, because increased CRF system activity drives alcohol drinking in rodents, we examined whether it predicted voluntary alcohol consumption as a function of prior stress exposure. Using a hypothalamic nuclear extract, we showed that the -248 T allele resulted in increased DNA protein interactions relative to the C allele. In vitro, the T allele resulted in CRH promoter activity that was higher following both stimulation with forskolin and treatment with dexamethasone. Endocrine and behavioral responses to social separation stress (release of ACTH and cortisol, and suppression of environmental exploration, respectively) were higher among carriers of the T allele, particularly among those exposed to early adversity in the form of peer rearing. We also found that T allele carriers with a history of early life adversity consumed more alcohol in a limited-access paradigm. Our data suggest that CRH promoter variation that confers increased stress reactivity increases the risk for alcohol use disorders in stress-exposed individuals.
Barr
Christina S
CS
Laboratory of Clinical and Translational Studies , National Institutes of Health/National Institutes on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA. cbarr@mail.nih.gov
Dvoskin
Rachel L
RL
Gupte
Manisha
M
Sommer
Wolfgang
W
Sun
Hui
H
Schwandt
Melanie L
ML
Lindell
Stephen G
SG
Kasckow
John W
JW
Suomi
Stephen J
SJ
Goldman
David
D
Higley
J Dee
JD
Heilig
Markus
M
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000428:Alcohol Drinking / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D014644:Genetic Variation; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D006854:Hydrocortisone / Q000097:blood; D008253:Macaca mulatta / Q000235:genetics* / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012931:Social Environment; D012934:Social Isolation; D013315:Stress, Psychological / Q000097:blood / Q000503:physiopathology / Q000523:psychology; D014162:Transfection
D049452:Green Fluorescent Proteins; D005576:Colforsin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone
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