Emerging evidence indicates that brain region-specific alteration of CREB signaling is also an important regulator involved in depression-like behavior that emerges during abstinence following alcohol drinking. As a key symptom of clinical depression, anhedonia reflects reduced interest in enjoying pleasure-seeking behavior and plays a key role in relapse (99, 100) and in the perpetuation of excessive alcohol consumption in dependent individuals (101). Important clinical evidence clearly demonstrated that the persistence and intensity of some behavioral withdrawal symptoms positively correlated with anhedonia scales in detoxified alcohol-dependent subjects (102), extending previous findings of strong correlation between anhedonia and substance-related symptoms particularly in detoxified opiate-dependent subjects (103). The presence of depression-related behavioral phenotypes during protracted abstinence was also reported in rodent models (104–106). In mice undergoing 2 weeks of abstinence from chronic alcohol consumption, the persistent increase in plasma corticosterone response and upregulation of GR expression correlated with the development of depressive-like phenotypes, including anhedonia and helplessness (105), and reduced hippocampal neurogenesis (104). Further, there are several lines of evidence that suggest that downregulation of BDNF–TrKB–CREB signaling pathway may serve as a common
