Rapid and Long-Lasting Antidepressant Action by Targeting Midbrain HCN Channels

通过靶向中脑 HCN 通道实现快速且持久的抗抑郁作用

• 批准号: 10201445
• 负责人: SCOTT JAMES RUSSO
• 金额: $ 45.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201445
• 关键词: Acute; Aftercare; Animals; Antidepressive Agents; Behavior; Behavioral; Brain; Cells; Chronic; Chronic stress; Clinical Research; Cyclic Nucleotides; Deep Brain Stimulation; Distress; Dopamine; Dose; Exhibits; Exposure to; Feeling suicidal; Follow-Up Studies; Hour; Hyperactivity; Impairment; In Vitro; Infusion procedures; Intraperitoneal Injections; Ketamine; Knowledge; Life; Link; Major Depressive Disorder; Medial; Mediating; Mental Depression; Midbrain structure; Modeling; Moods; Mus; Nucleus Accumbens; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiology; Prefrontal Cortex; Preparation; Property; Publishing; Regulation; Reporting; Research; Retina; Rewards; Rodent Model; Role; Scopolamine; Selective Serotonin Reuptake Inhibitor; Slice; Social Behavior; Social Conditions; Social Interaction; Specificity; Stress; System; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Ventral Tegmental Area; Work; antidepressant effect; base; burden of illness; conditioned place preference; cyclic-nucleotide gated ion channels; depressed patient; depression model; dopamine system; dopaminergic neuron; drug efficacy; drug mechanism; heart function; improved; in vivo; intraperitoneal; ivabradine; new therapeutic target; novel; optogenetics; preclinical study; response; side effect; social; social defeat; social deficits; suicidal; theories; treatment effect

PROJECT SUMMARY Current antidepressant medications for major depressive disorder (MDD) take several weeks to months to achieve therapeutic effect. This inevitable delay for drug efficacy not only prolongs distress and impairment for depressed patients, but is also life threatening for MDD patients with suicidal ideation. This delay has led to the widely accepted theory that the therapeutic efficacy of antidepressants can only be achieved by chronic treatments. However, an increasing body of clinical studies, including deep brain stimulation, ketamine and scopolamine therapies, has demonstrated the ability to regulate mood states within minutes to hours. These groundbreaking findings provide new hope in minimizing MDD disease burden. The main purpose of this application is to explore a novel drug target, which offers the potential for rapid antidepressant efficacy. There are early lines of evidence linking the midbrain dopamine system mechanistically in rapid depression treatment. Consistent with this, various studies showed that optogenetically activating or inhibiting dopamine neurons in the ventral tegmental area (VTA) circuits, a brain’s reward system, rapidly and bi-directionally regulated depression-related behaviors in rodent models of depression. In a repeated social defeat stress (RSDS) model of depression, we previously demonstrated that pharmacological inhibition of hyperpolarization- activated cyclic nucleotide-gated (HCN) channels in the VTA reversed the pathophysiological hyperactivity of VTA dopamine neurons and achieved antidepressant-like effects within one hour. In our initial follow-up studies, we find that one single intra-VTA infusion of a HCN blocker induces rapid and long-lasting antidepressant-like effects. The single infusion-induced antidepressant efficacy lasts ~2 weeks. Similarly, one single systemic administration (intraperitoneal injection) of this HCN blocker also induces rapid and ~2 weeks long antidepressant-like effects, which is evidently different from typical antidepressants such as SSRIs that took two weeks to gain antidepressant-like efficacy in the same model. Focusing on the rapid and long-lasting treatment effects, the overall objectives of this application are: (1) Drug Effect: to systematically define dose- dependent effects of three selected HCN blockers on the VTA dopamine neuron activity and depression- related behaviors; and (2) Drug Mechanism: to determine the cellular and circuit mechanisms that underlie the long-lasting antidepressant-like efficacy induced by a single exposure to HCN blockers. Upon the completion of this project, the proposed studies will provide highly novel HCN channel mechanisms for rapid and long-lasting treatment effects. Additionally, we also expect novel information to improve our knowledge of dopamine circuit mechanisms of depression.

项目概要 目前治疗重度抑郁症 (MDD) 的抗抑郁药物需要几周到几个月的时间才能见效。 达到治疗效果。这种不可避免的药物疗效延迟不仅延长了患者的痛苦和损害 抑郁症患者，但对于有自杀意念的重度抑郁症患者也有生命危险。这一延误导致了 广泛接受的理论认为，抗抑郁药的治疗效果只能通过慢性治疗才能实现 治疗。然而，越来越多的临床研究，包括深部脑刺激、氯胺酮和 东莨菪碱疗法已被证明能够在几分钟到几小时内调节情绪状态。这些 突破性的发现为减轻 MDD 疾病负担带来了新的希望。这样做的主要目的 该应用的目的是探索一种新的药物靶点，该靶点具有快速抗抑郁功效的潜力。那里 是早期证据表明中脑多巴胺系统与快速抑郁症有机制联系 治疗。与此相一致的是，各种研究表明光遗传学激活或抑制多巴胺 腹侧被盖区（VTA）回路中的神经元，这是大脑的奖励系统，快速且双向 调节抑郁症啮齿动物模型中与抑郁症相关的行为。在一次又一次的社会失败压力下 （RSDS）抑郁症模型，我们之前证明了超极化的药理抑制- VTA 中激活的环核苷酸门控 (HCN) 通道逆转了 VTA 多巴胺神经元在一小时内达到抗抑郁效果。在我们最初的后续行动中 研究中，我们发现单次 VTA 内注射 HCN 阻滞剂可快速且持久地诱导 抗抑郁样作用。单次输注诱导的抗抑郁药效可持续约 2 周。同样，一 这种 HCN 阻滞剂的单次全身给药（腹膜内注射）也可诱导快速和约 2 周的时间 长效抗抑郁样作用，这与典型的抗抑郁药（如 SSRIs）明显不同 在同一模型中花了两周时间才获得类似抗抑郁药的功效。注重快速、持久 治疗效果，本申请的总体目标是：（1）药物效应：系统地定义剂量- 三种选定的 HCN 阻滞剂对 VTA 多巴胺神经元活动和抑郁的依赖性影响 相关行为； (2) 药物机制：确定药物的细胞和回路机制 单次接触 HCN 阻滞剂即可产生持久的抗抑郁样功效。完成后 在这个项目中，拟议的研究将为快速和持久的提供高度新颖的HCN通道机制 治疗效果。此外，我们还期望新的信息能够提高我们对多巴胺回路的了解 抑郁症的机制。