Candidate functional genes within the withdrawal-negative affect stage include (see Table 2): CRF type 1 receptor (CRHR1) implicated in stress reactivity and negative emotionality. For example, animal studies found an innate up-regulation of the Crhr1 transcript, encoding the corticotropin-releasing hormone receptor 1 (CRH-R1), in several limbic brain areas of msP rats genetically selected for high alcohol preference. Up-regulation of Crhr1 was associated with a genetic polymorphism in the Crhr1 promoter, and was accompanied by increased CRH-R1 density. In addition, a selective CRH-R1 antagonist (antalarmin) significantly reduced oral operant alcohol self-administration and blocked stress-induced reinstatement in the high preference msP rat line. These animal studies support a functional association of variants within CRHR1 and alcohol dependence in human studies(Chen et al., 2010; Hansson et al., 2006; Hsu et al., 2012; Ray et al., 2013). FK506 binding protein 5 (FKBP5), a chaperone protein that regulates HPA axis function, is implicated in severity of withdrawal, childhood trauma, aggression and suicidal behavior (Bevilacqua et al., 2012; Huang et al., 2014). Opioid Receptor Kappa 1 subtype (OPRK1), is one of the major subtypes of opioid
