Nicotinic Acetylcholine Receptors in Anxiety and Depression

描述（由候选人提供）：大脑中尼古丁胆碱能信号的改变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，对缺乏特定尼古丁受体亚基的小鼠的研究表明，这些受体与焦虑和抑郁都有关系。因此，尼古丁和亚型特异性尼古丁药物对这些精神障碍的治疗潜力提供了一个丰富的研究领域。然而，由于缺乏理想的动物模型和易于穿过血脑屏障的亚型选择性配体，先前阻碍了对这一领域的研究。该基金配备了新型化合物和多种行为模型，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。首先，这些药物的急性和慢性效应将在焦虑和抑郁模型中进行研究（例如，新奇诱导的吞咽试验和强迫游泳试验）。此外，急性和慢性给药尼古丁、伐尼克兰和沙替丁-a对成人神经发生的影响，已被认为是抗抑郁作用的机制，将使用荧光激活细胞分选（FACS）方法检测治疗动物海马中BrdU标记的细胞。最后，放射配体结合和顺序免疫沉淀试验将被用来确定哪些尼古丁受体亚型被尼古丁配体给药改变，从而可能对这些行为和神经元效应负责。本研究的目的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，调查行为效应背后的分子相关性，以及检查和评估用于尼古丁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，并为尼古丁化合物在精神疾病和障碍治疗中的应用奠定基础。

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.