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

描述(申请人提供)：抑郁症被世界卫生组织确定为导致残疾的主要全球原因之一，并影响到15%-20%的人的一生。所有批准的抗抑郁药物都需要2-4周的治疗 效果会显现，30%-40%的抑郁症患者对目前的治疗没有足够的反应。迫切需要具有新作用机制的速效抗抑郁药。很少有药理药物能产生快速的抗抑郁作用。所有这些药物，包括非竞争性NMDA拮抗剂氯胺酮，都由于不良副作用而被批准临床使用。我们最近在慢性抗抑郁作用的小鼠模型上发现，选择性5-HT2C(5-HT2C)受体拮抗剂比5-羟色胺再摄取抑制剂产生更快的抗抑郁作用。该项目建议使用小鼠来确定5-HT2C拮抗剂快速起效的抗抑郁作用的机制。我们已经发现，5-HT2C拮抗剂短期治疗可诱导内侧前额叶皮质CREB磷酸化、BDNF表达和神经元重塑。我们建议使用综合和多学科的方法来进一步描述这些机制，包括行为、分子遗传学、生化、形态和药理学方法。具体目标1将确定5-HT2C拮抗剂处理诱导BDNF表达的机制。我们将研究5-HT2C受体阻断对mPFC中锥体能中间神经元与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，并将确定介导这一效应的特定多巴胺受体单体和异构体。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的抗抑郁作用。这项工作可以提供必要的证据，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体研究是合理的。重要的是，这项工作还可以确定新的靶点，为其开发新的快速起效的抗抑郁药物。鉴于缺乏关于快速起效抗抑郁药物作用背后的神经机制的知识，这些研究可以为这一现象提供关键的见解。总之，拟议的工作将为快速起效抗抑郁作用的潜在机制提供有价值的新见解，并导致新的治疗方法。

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.