As alcohol dependence evolves, alcohol consumption escalates. This is thought to be associated with a shift from alcohol consumption for rewarding, positively reinforcing properties, to intake driven by stress-dampening, negatively reinforcing alcohol effects. Recent data show that Ucn1 contributes to the progressive escalation of alcohol preference seen during long-term intermittent access (Giardino et al., 2012b), suggesting that, similar to the CRF/CRF1R system (Heilig and Koob, 2007), the Ucn/CRF2R system may also undergo neuroadaptations as addictive processes evolve. Interestingly, intra-amygdalar injections of the highly selective CRF2 ligand Ucn3 increased alcohol self-administration in non-dependent rats, but suppressed it in rats made chronically dependent on alcohol (Funk and Koob, 2007). An involvement of the Ucn/CRF2 system in dependence-related neuroadaptations is further supported by the observation that the expression of CRF2Rs in the amygdala was down-regulated following a history of alcohol dependence (Sommer et al., 2008).
