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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，抑郁症的主要药物治疗是抑制单胺神经递质突触再摄取的药物。尽管单胺神经递质在抗抑郁药功效中的重要性不容忽视，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制中发挥着作用。此外，当前抗抑郁治疗的局限性，包括大量无反应者，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化合物的潜在目标，特别是胆碱能系统的过度激活可能导致抑郁症的病理生理学。细胞、生理和行为水平的研究表明，多种抗抑郁药，包括三环类药物、选择性血清素 (5HT) 再摄取抑制剂和非典型抗抑郁药，都充当烟碱乙酰胆碱受体的非竞争性拮抗剂。最近，临床试验表明，烟碱拮抗剂美加明添加到选择性 5HT 再摄取抑制剂 (SSRI) 中，对单独使用 SSRI 无反应的人类抑郁症患者具有抗抑郁作用。在上一个资助期间，我们发现使用烟碱拮抗剂和高亲和力 nAChR 的低效部分激动剂干扰内源性 ACh 信号传导，在小鼠中具有抗抑郁样作用。我们还发现，人类抑郁症受试者表现出高亲和力 nAChR 的占有率下降，而 nAChR 数量没有变化，这表明乙酰胆碱水平增加可能会导致人类抑郁症。我们假设高亲和力神经元 nAChR 的拮抗作用是经典抗抑郁化合物作用机制的重要组成部分，此外，烟碱受体拮抗剂可能是新型治疗剂，可用于对当前药物治疗无反应的患者。我们目前基于上一个资助期获得的数据的假设是，基底外侧杏仁核中 ACh 信号传导的阻断以及海马中 5HT-1A 受体的活性介导了烟碱化合物的抗抑郁样作用。我们建议跟进这一假设，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杏仁核特定神经元亚型中的 nAChR 功能，识别突触前和突触后 5HT 受体，进一步研究烟碱类药物抗抑郁样作用背后的分子和神经机制。烟碱介导的抗抑郁作用所需的亚型，并确定钙调神经磷酸酶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：高达 50% 的抑郁症患者对现有的抗抑郁药物治疗没有反应，因此开发新药物来治疗这种严重的精神疾病至关重要。新的报告表明，限制大脑中尼古丁受体的活性可能会导致对百忧解等经典抗抑郁药无反应的患者产生抗抑郁反应，并且我们发现尼古丁受体阻滞剂在抗抑郁作用的小鼠模型中具有类似抗抑郁作用。我们建议确定导致这种效应的大脑区域和分子变化，以扩大我们对抑郁症患者功能失调的大脑回路的了解，并找到治疗对现有治疗没有反应的患者的新方法。