Functional CRH variation increases stress-induced alcohol consumption in primates

Area of Science:

• Neuroscience
• Genetics
• Behavioral Science

Background:

• Corticotropin-releasing factor (CRF) integrates stress responses.
• CRH gene variations may influence susceptibility to stress-related pathology.
• Increased CRF system activity is linked to alcohol consumption in rodents.

Purpose of the Study:

• To investigate the impact of a specific CRH promoter single nucleotide polymorphism (SNP) on stress response.
• To determine if this CRH gene variant predicts voluntary alcohol consumption in relation to prior stress exposure.

Main Methods:

• Analysis of DNA-protein interactions using hypothalamic nuclear extract.
• In vitro assessment of CRH promoter activity with forskolin and dexamethasone.
• Evaluation of endocrine and behavioral responses to social separation stress in macaques.

Main Results:

• The T allele of the CRH promoter SNP (-248C-->T) showed increased DNA-protein interactions and higher promoter activity.
• CRH T allele carriers exhibited heightened endocrine (ACTH, cortisol) and behavioral stress responses.
• T allele carriers with early life adversity consumed more alcohol.

Conclusions:

• CRH promoter variation conferring increased stress reactivity may elevate the risk for alcohol use disorders.
• This SNP influences stress response and alcohol consumption patterns, particularly in individuals with a history of adversity.
• Findings highlight the role of genetic variation in CRH in mediating the relationship between stress and alcohol use.