Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Biol Psychiatry. 2009 Dec 15;66(12):1139-46. doi: 10.1016/j.biopsych.2009.07.004. Epub 2009 Aug 28.
Organ transplant patients receive chronic administration of the calcineurin inhibitor cyclosporin-A (CsA) and demonstrate increased incidence of mood disorders. Significant calcineurin expression can be observed with immunohistochemistry in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. It is therefore important to determine whether chronic blockade of calcineurin might contribute to symptoms of anxiety and depression in these patients.
Pharmacological CsA and viral-mediated gene transfer (adeno-associated viral expression of short hairpin RNA [AAV-shRNA]) approaches were used to inhibit calcineurin activity globally and selectively in the amygdala of the mouse brain to determine the role of calcineurin in behaviors related to depression and anxiety.
Systemic inhibition of calcineurin activity with CsA or local downregulation of calcineurin levels in the amygdala with AAV-delivered shRNAs targeting calcineurin A increased behavioral measures of anxiety in both the elevated plus maze and light/dark tests with no changes in locomotor activity. In the forced swim and tail suspension models of depression-like behavior, calcineurin blockade in the amygdala increased immobility similarly to manipulations that lead to a depression-like phenotype.
Taken together, these data demonstrate that decreasing calcineurin activity in the amygdala increases anxiety- and depression-like behaviors. These studies suggest that chronic administration of CsA to organ transplant patients could have significant effects on anxiety and mood and that this should be recognized as a clinical consequence of treatment to prevent transplant rejection.
器官移植患者接受钙调神经磷酸酶抑制剂环孢素 A（CsA）的慢性给药，并表现出更高的情绪障碍发生率。免疫组织化学可观察到杏仁核中存在显著的钙调神经磷酸酶表达，杏仁核是一个与情绪障碍和焦虑相关行为有关的重要脑区。因此，确定钙调神经磷酸酶的慢性阻断是否会导致这些患者出现焦虑和抑郁症状非常重要。
采用药理学 CsA 和病毒介导的基因转移（腺相关病毒表达短发夹 RNA [AAV-shRNA]）方法，在小鼠大脑的杏仁核中全局性和选择性地抑制钙调神经磷酸酶活性，以确定钙调神经磷酸酶在与抑郁和焦虑相关的行为中的作用。
用 CsA 系统性抑制钙调神经磷酸酶活性或用靶向钙调神经磷酸酶 A 的 AAV 递送 shRNA 下调杏仁核中的钙调神经磷酸酶水平，均可增加高架十字迷宫和明暗测试中的焦虑行为测量指标，而运动活动没有变化。在强迫游泳和悬尾抑郁样行为模型中，杏仁核中钙调神经磷酸酶的阻断增加了不动性，与导致抑郁样表型的操作相似。
综上所述，这些数据表明，降低杏仁核中的钙调神经磷酸酶活性会增加焦虑和抑郁样行为。这些研究表明，器官移植患者长期使用 CsA 可能会对焦虑和情绪产生重大影响，这应被视为预防移植排斥反应的治疗的临床后果。
