Nicotinic Acetylcholine Receptors in Anxiety and Depression

焦虑和抑郁中的烟碱乙酰胆碱受体

• 批准号: 8114999
• 负责人: Jill R. Turner
• 金额: $ 5.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114999
• 关键词: Acute; Affect; Agonist; Alzheimer' s Disease; Animal Model; Animals; Antidepressive Agents; Anxiety; Anxiety Disorders; Area; Autistic Disorder; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Bromodeoxyuridine; Cell Cycle; Cell Proliferation; Cell Separation; Cell model; Cells; Chronic; Disease; Dose; Evaluation; Experimental Designs; Flow Cytometry; Goals; Grant; Hippocampus (Brain); Immunoprecipitation; Investigation; Label; Lead; Ligands; Mental Depression; Mental disorders; Methods; Modeling; Molecular; Mus; Neurons; Nicotine; Nicotinic Receptors; Pharmaceutical Preparations; Physiological; Psyche structure; Regimen; Relative (related person); Research; Role; Signal Transduction; Specificity; Staging; Swimming; Testing; Therapeutic; Therapeutic Uses; Tissues; Up-Regulation; adult neurogenesis; base; cholinergic; desensitization; drug discovery; neurogenesis; neuron development; novel; precursor cell; radioligand; receptor; subventricular zone; varenicline

DESCRIPTION (provided by candidate): Alterations in nicotinic cholinergic signaling in the brain have been implicated in numerous diseases and disorders, such as Alzheimer's disease (AD), autism, anxiety and depression. In addition, studies using mice lacking specific nicotinic receptor subunits have implicated these receptors in both anxiety and depression. Therefore, nicotine and subtype-specific nicotinic drugs present a rich area for investigation of their therapeutic potential in these mental disorders. However, a dearth of ideal animal models and subtype- selective ligands that easily cross the blood-brain barrier have previously hampered inquiry into this area. Equipped with novel compounds and a variety of behavioral models, this grant aims to examine the behavioral effects of nicotine and the nicotinic partial agonists, varenicline and sazetidine-A, in models of anxiety and depression as well as elucidate the molecular and cellular underpinnings of these behaviors. Initially, the acute and chronic effects of these drugs will be investigated in models of anxiety and depression (e.g., the novelty-induced hypophagia test and the forced swim test). Additionally, the effects of acute and chronic administration of nicotine, varenicline and sazetidine-A on adult neurogenesis, which has been implicated as mechanism for antidepressant action, will be examined using a fluorescently-activated cell sorting (FACS) method to detect BrdU labeled cells in hippocampi from treated animals. Finally, radioligand binding and sequential immunoprecipitation assays will be utilized to determine what nicotinic receptor subtypes are altered by nicotinic ligand administration and, thus, may be responsible for these behavioral and neuronal effects. The goal of this research is to identify new potential therapeutic uses of these drugs for disorders such as anxiety and depression, investigate the molecular correlates underlying the behavioral effects, as well as examine and evaluate the most appropriate behavioral models for use in nicotinic drug discovery. This research may ultimately lead to new therapies for depression and anxiety disorders, as well lay the groundwork for application of nicotinic compounds in the treatment of mental disease and disorders.

描述（由候选人提供）：大脑中烟碱胆碱能信号的改变与许多疾病和失调有关，例如阿尔茨海默病 (AD)、自闭症、焦虑和抑郁。此外，使用缺乏特定烟碱受体亚基的小鼠进行的研究表明，这些受体与焦虑和抑郁有关。因此，尼古丁和亚型特异性烟碱药物为研究其治疗这些精神障碍的潜力提供了丰富的领域。然而，由于缺乏理想的动物模型和容易穿过血脑屏障的亚型选择性配体，此前阻碍了对该领域的研究。这项拨款配备了新颖的化合物和各种行为模型，旨在研究尼古丁和烟碱部分激动剂伐尼克兰和萨泽替丁-A在焦虑和抑郁模型中的行为影响，并阐明这些作用的分子和细胞基础。行为。最初，将在焦虑和抑郁模型中研究这些药物的急性和慢性影响（例如，新奇引起的吞咽不足测试和强迫游泳测试）。此外，将使用荧光激活细胞分选 (FACS) 方法检测 BrdU 标记细胞，以检查急性和慢性服用尼古丁、伐尼克兰和萨泽替丁-A 对成人神经发生的影响（这已被认为是抗抑郁作用的机制）在接受治疗的动物的海马体中。最后，放射性配体结合和序贯免疫沉淀测定将用于确定烟碱配体给药改变哪些烟碱受体亚型，从而可能导致这些行为和神经元效应。这项研究的目的是确定这些药物治疗焦虑和抑郁等疾病的新的潜在治疗用途，研究行为影响背后的分子相关性，以及检查和评估用于烟碱类药物发现的最合适的行为模型。这项研究可能最终导致抑郁症和焦虑症的新疗法，并为烟碱化合物在精神疾病和障碍的治疗中的应用奠定基础。