Anesthetic-induced burst suppression as a novel antidepressant mechanism

摘要 耐药抑郁症与持续性的职业残疾有关，患抑郁症的风险大大增加 自杀，以及更高的医疗保健利用成本。电休克治疗(ECT)是一种有效的 药物抵抗型抑郁症的治疗，尽管由于记忆和认知的原因，它通常耐受性很差 损害及其作用机制仍然难以捉摸。几项临床研究表明，反复的， 短期接触挥发性麻醉剂异氟醚的抗抑郁效果相当于一个疗程的 ECT在耐药抑郁症患者中的应用。异氟醚的抗抑郁作用可能是由于 它能够引起皮层爆发抑制，这是一种独特的脑电模式，类似于后遗症脑电 ECT诱发的癫痫发作。最近，我们发现之前暴露在异氟醚中的剂量会导致爆炸 抑制减少了大鼠获得性无助的发生率，而同等剂量的氟烷， 未能引发突发抑制，没有。此R21应用程序寻求通过以下方式扩展这些初步调查结果 检验两个最重要的假设。首先，大脑皮层爆发抑制是必要的，而且可能足以 解释异氟醚的抗抑郁作用，第二，皮质爆发抑制和 异氟醚及相关麻醉药的抗抑郁作用依赖于ATP门控K+的激活 通道，一种明确与细胞能量和新陈代谢相耦合的电导。具体目标1、4 不同的麻醉药引起皮层爆发抑制的倾向不同，将评估它们的 逆转大鼠适应不良行为的能力，包括无助和快感缺乏，这些方面的模型 严重抑郁障碍的精神病理学。在具体目标2中，我们将确定选择性ATP- 门控K+通道拮抗剂能够阻断皮层猝发抑制以及这种抑制是否丧失 活性可以阻止异氟醚和相关药物在动物身上发挥抗抑郁药的作用。这些 实验有可能产生重要和直接的影响，因为它扩大了 可用于治疗药物抵抗性抑郁症的治疗药物，包括能够诱导 皮质猝发抑制以及通过识别用于药物开发的新靶点而开始， ECT的治疗效果和持续时间，但没有目前限制耐受性的副作用。

Abstract Medication-resistant depression is associated with persistent vocational disability, substantially higher risk of suicide, and higher health care utilization costs. Electroconvulsive therapy (ECT) is an effective course of treatment for medication-resistant depression although it is often poorly tolerated due to memory and cognitive impairment and its mechanism of action remains elusive. Several clinical studies have indicated that repeated, short-term exposure to the volatile anesthetic isoflurane has antidepressant efficacy equivalent to a course of ECT in patients with medication-resistant depression. The antidepressant actions of isoflurane may be due to its ability to elicit cortical burst suppression, a distinctive EEG pattern resembling the postictal EEG following ECT-induced seizures. Recently, we found that that prior exposure to isoflurane in doses that elicit burst suppression reduces the incidence of learned helplessness in rats while comparable doses of halothane, which fail to elicit burst suppression, did not. This R21 application seeks to extend these preliminary findings by testing two overarching hypotheses. First, that cortical burst suppression is necessary and possibly sufficient to explain the antidepressant actions of isoflurane and second that cortical burst suppression and the antidepressant efficacy of isoflurane and related anesthetics are dependent on activation of the ATP-gated K+ channel, a conductance explicitly coupled to cellular energetics and metabolism. In Specific Aim 1, four anesthetic drugs that differ in their propensity to elicit cortical burst suppression will be evaluated for their ability to reverse maladaptive behaviors, including helplessness and anhedonia, in rats that model aspects of psychopathology in major depressive disorder. In Specific Aim 2, we will determine whether selective ATP- gated K+ channel antagonists are capable of blocking cortical burst suppression and whether loss of this activity prevents isoflurane and related drugs from exerting their antidepressant-like effects in animals. These experiments have the potential to have an important and immediate impact by extending the short list of therapeutic agents available to treat medication-resistant depression to include drugs capable of eliciting cortical burst suppression and by identifying a novel target for the development of drugs with the onset, therapeutic efficacy and duration of ECT but without the side effects that currently limit tolerability.