paradigm that serves as a relapse analog (Molander et al., 2012). Results suggested that stress-induced augmentation of alcohol intake and escalation of alcohol intake was lower in the brain-specific knockout mice as compared to control animals. These findings indicate that the contribution of CRHR1 to basal alcohol intake and relapse-like drinking may be limited to situations with a high stress load, underscoring G × E effects for this locus. Further, a clinical study found that a CRHR1 SNP (rs110402; same as the one identified in this study) interacted with a Corticotropin releasing factor binding protein (CRHBP) SNP (rs3811939) to predict higher risk of comorbid alcoholism in a sample of patients with primary schizophrenia. Of interest, CRHR1 and CRHBP messenger RNA (mRNA) levels were quantified as a biological estimate of ligand efficiency of the CRF system and analyses revealed that these two markers were associated with blood mRNA levels across both alcohol dependent patients and non-dependent controls (Ribbe et al., 2011). Together, these recent studies emphasize the biological plausibility and provide initial mechanistic evidence that the CRF system and the CRHR1 gene in particular, is involved with alcoholism risk through interactions with the stress-pathway.
