Mechanisms underlying fast-onset antidepressant effects of 5-HT2C antagonists - R

5-HT2C 拮抗剂快速起效抗抑郁作用的机制 - R

• 批准号: 8579251
• 负责人: STEPHANIE C DULAWA
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-11 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8579251
• 关键词: Adverse effects; Affect; Antidepressive Agents; Behavioral; Biochemical; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Chronic; Clinical; Complex; Depressed mood; Development; Dopamine Receptor; Grant; Health; Hippocampus (Brain); Human; Individual; Interneurons; Ketamine; Knowledge; Lead; Medial; Mediating; Mental Depression; Molecular Genetics; Monoamine Oxidase Inhibitors; Mus; Muscarinic Acetylcholine Receptor; N-Methylaspartate; Neurons; Patients; Pharmaceutical Preparations; Phosphorylation; Prefrontal Cortex; Reporting; Role; Scopolamine; Second-Generation Antidepressive Agents; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Signaling Molecule; System; Testing; Therapeutic; Therapeutic Effect; Work; World Health Organization; burden of illness; disability; hippocampal pyramidal neuron; insight; interdisciplinary approach; monomer; mouse model; neuromechanism; novel; novel therapeutics; preclinical study; response; suicidal risk; transmission process

DESCRIPTION (provided by applicant): Depression is identified among the leading global causes of disability by the World Health Organization, and affects 15-20% of individuals during their lifetime. All approved antidepressants require 2 - 4 weeks of treatment for their therapeutic effects to emerge, and 30-40% of depressed subjects do not respond adequately to current treatments. Fast-onset antidepressants with novel mechanisms of action are greatly needed. Few pharmacological agents have been identified which induce rapid antidepressant effects. None of these, including the noncompetitive NMDA antagonist ketamine, are approved for clinical use due to adverse side effects. We recently found that selective serotonin 2C (5-HT2C) receptor antagonists produce substantially faster-onset antidepressant effects than serotonin reuptake inhibitors using mouse models of chronic antidepressant action. This project proposes to identify the mechanisms underlying the rapid-onset antidepressant effects of 5-HT2C antagonists using mice. We already found that short-term treatment with 5- HT2C antagonists induces CREB phosphorylation, BDNF expression, and neuronal remodeling in the medial prefrontal cortex. We propose to use an integrated and multidisciplinary approach to further delineate these mechanisms which includes behavioral, molecular genetic, biochemical, morphological, and pharmacological approaches. Specific Aim 1 will identify the mechanisms by which 5-HT2C antagonist treatment induces BDNF expression. We will examine the role of 5-HT2C receptor blockade on pyramidal vs. GABAergic interneurons in the mPFC. We will also examine the role of the dopaminergic system, and will identify the specific dopamine receptor monomer and heteromers mediating this effect. Specific Aim 2 will determine which signaling molecules downstream of BDNF induce neuronal remodeling and the antidepressant behavioral response. We will assess whether 5-HT2C antagonists and ketamine utilize the same signaling cascade downstream of BDNF to induce rapid antidepressant effects. This work could provide evidence required to justify human studies examining selective 5-HT2C antagonists as potential fast-onset antidepressants. Importantly, this work could also identify novel targets for which new fast-onset antidepressants could be developed. Given the dearth of knowledge regarding the neural mechanisms underlying fast-onset antidepressant effects, these studies could provide critical insights into this phenomenon. In summary, the proposed work will provide valuable new insights into the mechanisms underlying fast-onset antidepressant action and lead to novel treatments.

描述（由申请人提供）：世界卫生组织将抑郁症列为全球导致残疾的主要原因之一，并影响 15-20% 的人一生。所有批准的抗抑郁药都需要 2 - 4 周的治疗才能发挥作用 效果出现，30-40% 的抑郁症受试者对当前的治疗没有充分反应。非常需要具有新颖作用机制的速效抗抑郁药。很少有药物能够产生快速的抗抑郁作用。由于不良副作用，这些药物（包括非竞争性 NMDA 拮抗剂氯胺酮）均未获批准用于临床。我们最近使用慢性抗抑郁作用的小鼠模型发现，选择性血清素 2C (5-HT2C) 受体拮抗剂比血清素再摄取抑制剂产生显着更快的抗抑郁作用。该项目旨在利用小鼠确定 5-HT2C 拮抗剂快速起效抗抑郁作用的机制。我们已经发现，用5-HT2C拮抗剂进行短期治疗会诱导内侧前额叶皮质中的CREB磷酸化、BDNF表达和神经元重塑。我们建议使用综合的多学科方法来进一步描述这些机制，包括行为、分子遗传学、生物化学、形态学和药理学方法。具体目标 1 将确定 5-HT2C 拮抗剂治疗诱导 BDNF 表达的机制。我们将研究 5-HT2C 受体阻断对 mPFC 中锥体与 GABA 能中间神经元的作用。我们还将研究多巴胺能系统的作用，并将确定介导这种作用的特定多巴胺受体单体和异聚体。具体目标 2 将确定 BDNF 下游的哪些信号分子诱导神经元重塑和抗抑郁行为反应。我们将评估 5-HT2C 拮抗剂和氯胺酮是否利用 BDNF 下游相同的信号级联来诱导快速抗抑郁作用。这项工作可以提供证明选择性 5-HT2C 拮抗剂作为潜在的快速起效抗抑郁药的人类研究合理性所需的证据。重要的是，这项工作还可以确定新的靶标，从而开发新的速效抗抑郁药。鉴于缺乏关于快速起效的抗抑郁作用背后的神经机制的知识，这些研究可以为这种现象提供重要的见解。总之，拟议的工作将为快速起效抗抑郁作用的机制提供有价值的新见解，并带来新的治疗方法。