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）：抑郁症是世界卫生组织确定的全球主要致残原因之一，在其一生中影响15-20%的人。所有被批准的抗抑郁药都需要2 - 4周的治疗