Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice
Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice
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DOI：
10.1038/npp.2008.90
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发表时间：
2009-04
影响因子：
7.6
通讯作者：
J. R. Stevenson;J. Schroeder;K. Nixon;J. Besheer;F. Crews;C. Hodge
中科院分区：
文献类型：
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作者：
J. R. Stevenson;J. Schroeder;K. Nixon;J. Besheer;F. Crews;C. Hodge
酒精中毒和抑郁表现出高度的共病。临床证据还表明，在长期戒酒期间出现的抑郁症对复发的负面影响比先前存在的抑郁症更大。虽然没有单一的神经生物学机制可以解释与这些破坏性疾病相关的行为病理，但越来越多的证据表明，酗酒和抑郁的各个方面都与海马神经发生的减少有关。在这里，我们报告了一个新的临床前行为模型的结果，该模型显示，自愿戒酒会导致抑郁样行为的出现和神经发生的减少。C57BL/6J小鼠在家笼中自行给药乙醇（10% v/v） vs h2o 28 d。然后将酒精去除1天或14天，然后对小鼠进行强迫游泳测试，以测量抑郁样行为。戒酒14天后，而不是1天后，小鼠表现出明显的抑郁样行为。禁欲期间抑郁样行为的显著增加与海马齿状回中增殖细胞核抗原（PCNA）和双皮质素（DCX）免疫反应性的降低有关，表明增殖神经祖细胞（NPC）和未成熟神经元的数量分别减少。在酒精暴露开始时用溴脱氧尿苷（BrdU）标记的npc数量没有改变，这表明npc的生存与戒断诱导的抑郁症无关。在戒断期间使用抗抑郁药地西帕明进行慢性治疗（14天）可以防止抑郁样行为的出现和海马神经发生的减少，这表明戒断诱导的抑郁与海马的结构可塑性有关。总的来说，本研究的结果支持以下结论，即戒酒期间会发生深刻的功能（即行为）和结构变化，并表明抗抑郁治疗可能会减轻一些病理性神经行为适应。
Alcoholism and depression show high degrees of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse than pre-existing depression. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in hippocampal neurogenesis. Here, we report results from a novel preclinical behavioral model showing 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 H 2 O in the home cage for 28 days. Alcohol was then removed for 1 or 14 days, 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 proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus indicating that both the number of proliferating neural progenitor cells (NPC) and immature neurons were reduced, respectively. The number of NPCs that were labeled with bromo-deoxyuridine (BrdU) at the beginning of alcohol exposure was not altered indicating that survival of NPCs is not linked to abstinence-induced depression. Chronic treatment (14 days) with the antidepressant desipramine during abstinence prevented both the emergence of depression-like behavior and the reduction in hippocampal neurogenesis indicating that abstinence-induced depression is associated with structural plasticity in the hippocampus. Overall, the results of this study support the conclusion that profound functional (ie behavioral) and structural changes occur during abstinence from alcohol use and suggest that antidepressant treatment may alleviate some of these pathological neurobehavioral adaptations.