Anesthetic-induced burst suppression as a novel antidepressant mechanism

摘要 抗药性抑郁症与持续的职业残疾有关， 自杀和更高的医疗保健使用成本。电休克治疗（ECT）是一种有效的治疗方法， 治疗抗药性抑郁症，尽管由于记忆和认知障碍， 损伤及其作用机制仍然难以捉摸。一些临床研究表明，重复， 短期暴露于挥发性麻醉剂异氟烷的抗抑郁疗效相当于一个疗程的 抗抑郁症患者的ECT。异氟烷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图模式，类似于以下癫痫发作后的脑电图 ECT诱导的癫痫发作。最近，我们发现，预先暴露于异氟醚的剂量， 抑制降低了大鼠习得性无助的发生率，而可比较剂量的氟烷， 未能引起爆发抑制，没有。本R21申请旨在通过以下方式扩展这些初步调查结果： 测试两个首要假设首先，皮层爆发抑制是必要的，可能足以 解释异氟烷的抗抑郁作用，其次解释皮质爆发抑制和 异氟烷和相关麻醉剂的抗抑郁疗效依赖于ATP门控K+的激活 通道，电导明确耦合到细胞能量和代谢。在具体目标1中， 麻醉药物引起皮质爆发抑制的倾向不同，将评估其 逆转适应不良行为的能力，包括无助和快感缺乏，在大鼠模型中， 重度抑郁症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质爆发抑制， 活性阻止异氟烷和相关药物在动物中发挥其抗抑郁样作用。这些 实验有可能通过扩大短名单产生重要和直接的影响， 可用于治疗耐药性抑郁症的治疗剂包括能够引起 皮质爆发抑制和通过确定一个新的目标，为开发药物的发病， 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.