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

项目总结 目前治疗重度抑郁障碍(MDD)的抗抑郁药物需要几周到几个月的时间才能 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 对于有自杀念头的MDD患者来说，这不仅是一种危险，也是一种威胁生命的疾病。这一延误导致了 被广泛接受的理论认为，抗抑郁药物的治疗效果只能通过慢性 治疗。然而，越来越多的临床研究，包括脑深部刺激，氯胺酮和 东莨菪碱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 突破性的发现为将MDD疾病负担降至最低带来了新的希望。这样做的主要目的是 应用是探索一种新的药物靶点，它提供了快速抗抑郁疗效的潜力。那里 早期证据表明快速抑郁与中脑多巴胺系统有机械性联系 治疗。与此一致的是，各种研究表明，光基因激活或抑制多巴胺 腹侧被盖区(VTA)回路中的神经元，大脑的奖励系统，快速和双向的 在抑郁的啮齿动物模型中调节抑郁相关行为。在一次又一次的社会失败压力中 (RSD)抑郁症模型，我们先前证明了药物对超极化的抑制作用。 激活的环核苷酸门控(HCN)通道逆转VTA的病理生理亢进 VTA多巴胺能神经元在1小时内达到抗抑郁药样作用。在我们最初的后续行动中 研究发现，一次VTA内输注一种HCN阻滞剂可引起快速而持久的效应 抗抑郁药样作用。单次输注诱导的抗抑郁药效持续时间为2周。类似地，一个 单次全身给药(腹腔注射)这种HCN阻滞剂也会引起快速和~2周的 长时间的抗抑郁药样作用，这明显不同于典型的抗抑郁药，如SSRIs 在相同的模型中，花了两周的时间才获得类似抗抑郁药的疗效。关注快速和持久的 治疗效果，本申请的总体目标是：(1)药物效果：系统地定义剂量-- 三种HCN阻滞剂对VTA多巴胺神经元活性和抑郁的依赖效应 相关行为；以及(2)药物机制：确定作为基础的细胞和电路机制 单次接触HCN阻滞剂可产生持久的抗抑郁药样疗效。在完成后 本项目所提出的研究将为快速和持久的HCN通道机制提供高度新颖的 治疗效果。此外，我们还期待新的信息来提高我们对多巴胺回路的了解。 抑郁的机制。

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.