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: 7753963
• 负责人: Jill R. Turner
• 金额: $ 4.72万
• 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/7753963
• 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 disorders; Methods; Modeling; Molecular; Mus; Neurons; Nicotine; Nicotinic Receptors; Pharmaceutical Preparations; Physiological; Psyche structure; Relative (related person); Research; Role; Signal Transduction; Specificity; Staging; Swimming; Testing; Therapeutic; Therapeutic Uses; Tissues; Treatment Protocols; Up-Regulation; adult neurogenesis; base; cholinergic; depression; 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Candiate提供)：大脑中尼古丁胆碱能信号的变化与许多疾病和障碍有关，如阿尔茨海默病(AD)、自闭症、焦虑和抑郁。此外，利用缺乏特定烟碱受体亚单位的小鼠进行的研究表明，这些受体与焦虑和抑郁有关。因此，尼古丁和特定亚型尼古丁药物为研究它们在这些精神障碍中的治疗潜力提供了一个丰富的领域。然而，缺乏理想的动物模型和容易跨越血脑屏障的亚型选择性配体，以前阻碍了对这一领域的研究。这项拨款配备了新的化合物和各种行为模型，旨在研究尼古丁和尼古丁部分激动剂varenicline和sazetidine-A在焦虑和抑郁模型中的行为影响，并阐明这些行为的分子和细胞基础。最初，这些药物的急性和慢性影响将在焦虑和抑郁的模型中进行调查(例如，新奇诱导的低吞噬试验和强迫游泳试验)。此外，急性和长期给予尼古丁、varenicline和sazetidine-A对成年神经发生的影响，这已被认为是抗抑郁作用的机制，将使用荧光激活细胞分类(FACS)方法检测处理动物海马区的BrdU标记细胞。最后，放射配基结合和顺序免疫沉淀分析将被用来确定尼古丁受体亚型被尼古丁配体注射改变，从而可能对这些行为和神经元效应负责。这项研究的目标是确定这些药物对焦虑和抑郁等疾病的新的潜在治疗用途，调查潜在的行为影响的分子相关性，以及检查和评估用于尼古丁药物开发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，并为尼古丁化合物在精神疾病和障碍治疗中的应用奠定基础。