Continued high alcohol use and intermittent alcohol withdrawal generates a negative emotional state that leads to continued alcohol use and addiction. Corticotrophin releasing factor (CRF) plays a central role in stress-related alcohol seeking. CRF release in the central nucleus of the amygdala (CNA) is increased during alcohol withdrawal in alcohol dependant rats and alcohol withdrawal anxiety like symptoms are reduced by injection of CRF-1 receptor antagonists into the CNA. CRF deletion or CRF -1 receptor antagonists reduce alcohol self-administration in dependent but not in nondependent animals, Increased CRF-1 receptor density in several brain areas is associated with increased shock induced alcohol intake in alcohol preferring rats and this is blocked by a CRF-1 receptor antagonist. Rhesus monkeys who have a gene variant with increased CRF promoter activity and also monkeys with a variant with decreased sensitivity of the CRF promoter to glucocorticoids have increased alcohol consumption. In humans with a genetic variation in the CRF receptor, early life stress produces early onset of drinking and increased drinking. Taken together, this indicates that genetic variations that increase activity of the CRF system increase alcohol intake.
A variation in the CRF receptor increases alcohol seeking which responds to a CRF antagonist treatment.

A genetic variation in the CRH 1 Receptor gene in msP alcohol preferring rats is associated with increased CRH Receptor mRNA and receptor density, a lower threshold for shock induced reinstatement of alcohol seeking and an increased response to the CRH 1 Receptor antagonist antalarmin.

Marchigian-Sardinian preferring rat (msP) was selected for high alcohol preference for over 50 generations. Two single nucleotide polymorphism were identified in the CRH receptor gene in msP rats. The increased CRH Receptor 1 mRNA and density was seen in many brain areas. The msP rats had increased freezing in fear-conditioning compared to Wistar rats and antalarmin decreased alcohol intake in msP rats and not in Wistar rats.(Constructed from data in Hansson, A.C. et al. PNAS, 103: 5236 - 5241, 2006)©2009 NBEP
A CRF gene variant increases alcohol drinking following stress.

A CRF Gene Variant with Increased CRF Promoter Activity Is Associated with Increased HPA Response to Stress and Increased Alcohol Drinking in Rhesus Monkeys Who Had Early Maternal Deprivation

Peer reared monkeys were hand reared for the first 37 days and peer reared until 8 months. Social separation stress was four, 4 day separation age 6 – 7 months, alcohol intake was at age 3.5 – 5 years, limited access for 1 month. C/T peer reared monkeys also had decreased exploration during periods of social isolation stress.(Constructed from data in Barr, C.S. et al. PNAS, 106: 14593 - 98, 2009)©2009 NBEP
A genetic variant that decreases glucocorticoid feedback to the CRH system makes monkeys more bold and increases alcohol drinking

A SNP (C/G) that Decreases Sensitivity of the CRH Promoter to Glucocorticoids Is Associated with More Curious/Bold Responding to an Unfamiliar Male and Increased Alcohol Consumption

Male adolescents and adult Rhesus monkeys were exposed to an unfamiliar male monkey and curious/bold behavior was rated. The ratings of explore/bold were also higher for home cage behavior in C/G monkeys as infants. Monkeys with the C/G haplotype also had increased plasma ACTH and decreased CSF CRH levels in the non-stressed state.(Constructed from data in Barr, C.S. et al. Arch Gen Psychiatry, 65: 934 - 944, 2009)©2009 NBEP
Stress interacts with a CRF receptor variant to produce early onset drinking and increased heavy drinking.

A Genetic Variation in the Corticotrophin Releasing Hormone Receptor (CRHR1) Leads to Earlier Onset of Drinking Alcohol and Increased Heavy Drinking in Adolescents with Early Life Stress

(A) From prospective longitudinal study of at risk children assed from 3 months to 19 years of age, stressful life events assessed in the Munich Events List. (Constructed from data in Schmid, B. et al. Int J Neuropsychopharmacology, 13: 703, 2010)(B) From the same study of A. Heavy drinking defined as having drunk more than 5 (females 4) standard drinks (8-12g alcohol) in a row.(Constructed from Blomeyer, D. et al. Biol Psychiatry, 63: 146, 2008) ©2010 NBEP