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

基本信息

批准号：
10405032
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
项目类别：
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/10405032
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

项目摘要

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.

项目摘要当前用于重度抑郁症（MDD）的抗抑郁药需要数周到数月达到治疗效果。这种药物效率的必然延迟不仅延长了困扰和损害抑郁症患者，但也对具有自杀想法的MDD患者危及生命。这个延迟导致了广泛接受的理论，即只有慢性才能实现抗抑郁药的治疗效率治疗。然而，越来越多的临床研究，包括深脑刺激，氯胺酮和 Scopolamine疗法已经证明了在几分钟到几个小时内调节情绪状态的能力。这些开创性的发现为最小化MDD疾病伯恩提供了新的希望。主要目的应用是探索一种新型的药物靶标，该靶标提供了快速抗抑郁效率的潜力。那里是在快速抑郁症机械上与中脑多巴胺系统联系起来的早期证据治疗。与此一致，各种研究表明，光源激活或抑制多巴胺腹侧对段区域（VTA）电路的神经元，大脑的奖励系统，迅速和方向啮齿动物抑郁模型中的调节抑郁症与行为受到调节。在反复的社会失败压力下（RSD）抑郁模型，我们先前证明了药物对超极化的抑制作用 - VTA中活化的环肽门控通道（HCN）通道逆转了病理生理多动症 VTA多巴胺神经元并在一小时内实现了抗抑郁药样作用。在我们的最初随访中研究，我们发现HCN阻滞剂的一次单一VTA输注可引起快速和持久抗抑郁药样作用。单一输注诱导的抗抑郁效率持续约2周。同样，一个该HCN阻滞剂的单系统给药（腹膜内注射）也会诱导快速且〜2周长长的抗抑郁药样作用，显然与典型的抗抑郁药（如SSRI）有所不同在同一模型中，花了两个星期的时间才能获得抗抑郁药样效率。专注于快速而持久的治疗效果，本应用的总体目标是：（1）药物效应：系统地定义剂量 - 三个选定的HCN阻滞剂对VTA多巴胺神经元活性和抑郁的依赖性影响 - 相关行为；（2）药物机制：确定基于的细胞和电路机制一次暴露于HCN阻滞剂引起的持久抗抑郁样效率。完成后该项目，拟议的研究将为快速和持久提供高新颖的HCN通道机制治疗效果。此外，我们还期望新的信息可以提高我们对多巴胺电路的了解抑郁机制。