Anesthetic-induced burst suppression as a novel antidepressant mechanism

麻醉引起的爆发抑制作为一种新型抗抑郁机制

• 批准号: 9283616
• 负责人: Gregory I Elmer
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283616
• 关键词: Adverse effects; Anesthesia procedures; Anesthetics; Anhedonia; Animal Model; Animals; Antidepressive Agents; Behavior; Cerebrovascular Circulation; Chloral Hydrate; Clinical Research; Consumption; Coupled; Data; Depressed mood; Development; Dose; Drug effect disorder; Electroconvulsive Therapy; Electroencephalography; Exhibits; Exposure to; Generations; Halothane; Hour; Impaired cognition; Incidence; Isoflurane; Lead; Learned Helplessness; Life; Major Depressive Disorder; Mediating; Memory impairment; Mental Depression; Metabolism; Modeling; Neurons; New Agents; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Potassium Channel; Pre-Clinical Model; Propofol; Psychopathology; Rattus; Reporting; Resistance; Risk; Rodent; Role; Sedation procedure; Seizures; Shock; Specific qualifier value; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; antidepressant effect; channel blockers; cost; disability; drug development; experimental study; health care service utilization; high risk; new therapeutic target; novel; phenomenological models; prevent; suicidal risk

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.

抽象的 耐药性抑郁症与持续的职业障碍有关，大大更高的风险 自杀和更高的医疗保健利用成本。电击疗法（ECT）是有效的过程 耐药性抑郁症的治疗通常由于记忆和认知而耐受性不佳 障碍及其行动机制仍然难以捉摸。几项临床研究表明，重复 短期暴露于挥发性麻醉的异氟烷具有抗抑郁剂的功效，等效于疗程 耐药性抑郁症患者的ECT。异氟烷的抗抑郁作用可能是由于 它引起皮质爆发抑制的能力，一种独特的脑电图模式，类似于postictal eeg。 ECT诱导的癫痫发作。最近，我们发现先前暴露于引起爆发的剂量的异氟烷 抑制可降低大鼠学习的无助性的发生率，而可比的氟烷剂量 无法引起爆发的抑制。该R21应用程序旨在通过 测试两个总体假设。首先，这种皮质爆发抑制是必要的，并且可能足以 解释异氟烷的抗抑郁作用，其次是皮质爆发抑制和 异氟烷和相关麻醉剂的抗抑郁疗法取决于ATP门控k+的激活 通道，一种与细胞能量和新陈代谢明确耦合的电导。在特定的目标1中，四个 将评估其引起皮质爆发抑制倾向的麻醉药物 在模拟的大鼠中，能够扭转适应不良行为，包括无助和抗痛苦的行为 主要抑郁症的心理病理学。在特定目标2中，我们将确定是否有选择性ATP- 门控k+通道拮抗剂能够阻止皮质爆发抑制以及是否丢失 活性可防止异氟烷和相关药物在动物中发挥抗抑郁样作用。这些 实验有可能通过扩展简短清单来产生重要和直接的影响 治疗剂可用于治疗耐药性抑郁症以包括能够引起的药物 皮质爆发抑制，并通过确定新的靶标，以发作发育， ECT的治疗功效和持续时间，但没有目前限制耐受性的副作用。