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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.

项目总结