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Although many alcoholics experience periods of abstinence, most will relapse. Indeed, the inability to resist alcohol drinking is central to alcohol addiction. The emergence of negative affective states during abstinence is thought to be a key mediator of relapse behavior. The data presented here indicate that abstinence from voluntary alcohol drinking leads to the emergence of depression-like behavior and reductions in neurogenesis. C57BL/6J mice were allowed to self-administer ethanol (10% v/v) vs H2O in the home cage for 28 days. Alcohol was then removed for 1-d or 14-d, and mice were tested in the forced swim test to measure depression-like behavior. After 14 days, but not 1 day of abstinence from alcohol drinking, mice showed a significant increase in depression-like behavior. The significant increase in depression-like behavior during abstinence was associated with a reduction in neurogenesis. Chronic treatment (14-d) with the antidepressant desipramine during abstinence prevented both the emergence of depression-like behavior and the reduction in new neurons indicating that abstinence-induced depression is associated with structural plasticity in the hippocampus. Alterations in CREB expression and CREB activation, as measured by CREB and pCREB immunoreactivity, have been linked to changes in alcohol reinforcement, as well as depression; therefore, the changes in CREB in response to desipramine or vehicle treatment were investigated during the abstinence period. The most significant changes noted were in the CA3 subregion of the hippocampus which showed significant reduction in CREB and pCREB immunoreactivity due to 14-d abstinence, and complete prevention of this reduction by desipramine treatment. Dysregulation of the HPA axis is examined in this dissertation not only because it can lead to depression, but also because alcohol drinking, alcohol withdrawal, and alcohol abstinence are all associated with HPA axis dysregulation. Changes in the HPA axis as a result of 14-d abstinence were not evident. Overall, the results of this study support the conclusion that profound functional (i.e., behavioral) and structural changes occur during abstinence from alcohol use and suggest that antidepressant treatment may alleviate some of these pathological neurobehavioral adaptations.