Antidepressant Effect of Nicotinic Receptor Blockade

烟碱受体阻断的抗抑郁作用

基本信息

批准号：
8186338
负责人：
Marina R Picciotto
金额：
$ 41.38万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8186338
关键词：
8-Hydroxy-2-(di-n-propylamino)tetralin Address Affective Affinity Agonist Amygdaloid structure Antidepressive Agents Anxiety Area Behavior Behavioral Biochemical Brain Brain region Breeding Calcineurin Calcium Cholinergic Agents Cholinesterase Inhibitors Clinical Trials Complex Data Dependovirus Depressed mood Development Drosophila acetylcholine receptor alpha-subunit FOS gene Functional disorder Funding Hippocampus (Brain)Human Hyperactive behavior Individual Infusion procedures Ligands Mecamylamine Mediating Mental Depression Molecular Molecular Genetics Mood Disorders Mus Muscarinics Neurons Neuropharmacology Neurotransmitters Nicotine Nicotinic Agents Nicotinic Antagonists Nicotinic Receptors Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Physiological Physostigmine Play Prozac Rattus Reporting Research Rodent Role Second-Generation Antidepressive Agents Selective Serotonin Reuptake Inhibitor Serotonin Signal Pathway Signal Transduction Site Staining method Stains Stress Swimming Symptoms Synapses System Testing Therapeutic Therapeutic Agents base calcineurin phosphatase cholinergic cytisine depressive symptoms discount follow-up in vitro activity in vivo inhibitor/antagonist monoamine mouse model neurotransmission novel novel therapeutics receptor response reuptake small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): The primary pharmacological treatment for depression over the past several decades has been drugs that inhibit synaptic reuptake of monoamine neurotransmitters. Although the importance of monoamine neurotransmission in antidepressant efficacy cannot be discounted, recent evidence indicates other neurotransmitter systems certainly play a role in the mechanism of action of antidepressants. Furthermore, the limitations of current antidepressant treatments, including a large group of non-responders, necessitate the development of novel compounds to treat depression. A growing body of evidence suggests that cholinergic systems may be potential targets for the development of novel antidepressant compounds, and in particular, that excessive activation of cholinergic systems may contribute to the pathophysiology of depression. Studies at the cellular, physiological and behavioral levels have shown that a wide range of antidepressants, including tricyclics, selective serotonin (5HT) reuptake inhibitors, and atypical antidepressants, all act as non-competitive antagonists of nicotinic acetylcholine receptors. More recently, clinical trials have shown that the nicotinic antagonist mecamylamine has antidepressant effects when added to a selective 5HT reuptake inhibitor (SSRI) in human depressed patients non-responsive to the SSRI alone. In the last funding period we showed that interfering with endogenous ACh signaling using both nicotinic antagonists and low efficacy partial agonists of high affinity nAChRs had antidepressant-like effects in mice. We have also found that human depressed subjects show decreased occupancy of high affinity nAChRs with no change in nAChR number, suggesting that increased ACh levels may contribute to human depression. We have hypothesized that antagonism of high affinity neuronal nAChRs is an important component of the therapeutic mechanism of action of classical antidepressant compounds, and further, that nicotinic receptor antagonists may be novel therapeutic agents that could be useful in patients who are not responsive to current pharmacological treatments. Our current hypothesis based on data obtained in the last funding period is that blockade of ACh signaling in the basolateral amygdala along with activity of 5HT-1A receptors in the hippocampus mediate the antidepressant- like effects of nicotinic compounds. We propose the to follow up on this hypothesis and to investigate further the molecular and neuronal mechanisms underlying the antidepressant-like effect of nicotinic drugs by determining whether the antidepressant-like effects of nicotinic antagonists and partial agonists depend on nAChR function in specific neuronal subtypes in the amygdala, identifying pre- and post-synaptic 5HT receptor subtypes necessary for nicotinic-mediated antidepressant effects and determining whether calcineurin activity is essential for the antidepressant-like effects of nicotinic compounds. PUBLIC HEALTH RELEVANCE: Up to 50% of patients with depression are non-responsive to existing antidepressant therapies so it is essential that new medications are developed to treat this crippling psychiatric illness. Emerging reports show that limiting the activity of nicotine receptors in the brain can result in an antidepressant response in patients who were not responsive to a classical antidepressant like Prozac and we have found that nicotine receptor blockers are antidepressant-like in mouse models of antidepressant effects. We propose to identify the brain regions and molecular changes that are responsible for this effect to enlarge our understanding of the brain circuits that are dysfunctional in patients with depression and to find new ways to treat patients who do not respond to existing treatments.

描述（由申请人提供）：过去几十年来，抑郁症的主要药理治疗方法是抑制单胺神经递质突触再摄取的药物。尽管单胺神经传递在抗抑郁药疗效中的重要性无法降低，但最近的证据表明，其他神经递质系统肯定在抗抑郁药的作用机理中起作用。此外，包括大量非反应者在内的当前抗抑郁治疗的局限性需要开发新的化合物来治疗抑郁症。越来越多的证据表明，胆碱能系统可能是开发新型抗抑郁药化合物的潜在靶标，尤其是胆碱能系统的过度激活可能有助于抑郁症的病理生理学。在细胞，生理和行为水平上的研究表明，包括三轮车，选择性5-羟色胺（5HT）再摄取抑制剂和非典型抗抑郁药在内的广泛抗抑郁药作用，都是尼古丁乙酰胆碱受体的非竞争力拮抗剂。最近，临床试验表明，烟碱性拮抗剂梅卡米胺在人类抑郁症患者中对SSRI无反应的人类抑郁症患者的选择性5HT再摄取抑制剂（SSRI）时具有抗抑郁作用。在最后的资金期间，我们表明，使用烟碱拮抗剂和低亲和力NACHR的低疗法部分激动剂干扰内源性ACH信号，对小鼠具有抗抑郁样作用。我们还发现，人类抑郁症受试者显示出高亲和力NACHR的占用率降低而NACHR数量没有变化，这表明ACH水平升高可能导致人类抑郁症。我们假设高亲和力神经元NACHRS是经典抗抑郁药化合物作用的治疗机制的重要组成部分，此外，烟碱受体拮抗剂可能是新型的治疗剂，可能对对当前药理治疗无反应的患者有用。我们目前基于在上一资金期间获得的数据的当前假设是基底外侧杏仁核中ACH信号传导的封锁以及海马中5HT-1A受体的活性介导了烟碱化合物的抗抑郁剂类似作用。我们建议对这一假设进行跟进，并通过确定烟碱拮抗剂和部分激动剂的抗抑郁样作用是否依赖于nACHR在特定的神经元亚型中的抗抑郁样作用，以进一步研究烟碱药物抗抑郁药的抗抑郁样作用的基础分子和神经元机制。烟碱介导的抗抑郁作用所必需的亚型，并确定钙调蛋白活性是否对于烟碱化合物的抗抑郁样作用至关重要。公共卫生相关性：多达50％的抑郁症患者对现有的抗抑郁药疗法无反应，因此必须开发出新的药物来治疗这种严重的精神病。新兴报告表明，限制大脑中尼古丁受体的活性可能会导致对像百忧解这样的经典抗抑郁药反应的患者的抗抑郁反应，并且我们发现尼古丁受体阻滞剂在抗抑郁剂效应的小鼠模型中是抗抑郁药样的。我们建议确定造成这种影响的大脑区域和分子变化，以增强我们对抑郁症患者功能失调的大脑回路的理解，并找到治疗对现有治疗的患者的新方法。