压力的增加可能导致大脑神经信号的汇聚，触发促肾上腺皮质激素释放因子（CRF）的释放。而这又会引发激活身体对于压力的紧急自主和行为响应的分子的释放，后者是由CRH基因编码到。但是太多的CRH神经递质可能导致诸如抑郁症、创伤后应激障碍以及酒精依赖等疾病。在大鼠身上，CRF肽系统的过度激活导致了更高的酒精摄入。

Christina Barr及其同事调查了CRH基因的一个突变是否会对在幼年时接触到压力的成年猕猴的酒精使用产生影响。这组作者发现，携带T版本（在猕猴身上发现的启动子单核苷多态）的这种基因的猕猴比携带“C”版本等位基因的猕猴在压力下表现得更焦虑。这组作者也证明了那些携带T版本的猴子比携带C突变的猴子具有更高水平的这种压力基因和更高的酒精摄入。这组作者提出，CRH基因突变可能充当酒精滥用或早发型酒瘾的风险因子。

这组科学家说，阻断CRH活动的药物可以作为治疗酒精依赖的一种疗法。

推荐原始出处：

PNAS August 17, 2009, doi: 10.1073/pnas.0902863106

Functional CRH variation increases stress-induced alcohol consumption in primates

Christina S. Barra,1,2, Rachel L. Dvoskina,1, Manisha Guptea,b, Wolfgang Sommera, Hui Suna, Melanie L. Schwandta, Stephen G. Lindella, John W. Kasckowc, Stephen J. Suomid,1, David Goldmanb,1, J. Dee Higleye,1 and Markus Heiliga,1

aLaboratory of Clinical and Translational Studies and
bLaboratory of Neurogenetics, National Institutes of Health/National Institutes on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
cVA Pittsburgh Health Care System MIRECC and Behavioral Health and Western Psychiatric Institute and Clinics, University of Pittsburgh Medical Center Western Psychiatric Institute and Clinics, University of Pittsburgh Medical Center, Pittsburgh, PA 15206;
eDepartment of Psychology, Brigham Young University, 1042 SWKT, Provo, UT, 84602; and
dLaboratory of Comparative Ethology, National Institutes of Health/National Institute of Child Health and Human Development, Poolesville, MD, 20837

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.