The 5-HT7 receptor in models of psychiatric disorders

描述(申请人提供)：5-HT7受体是最近发现的5-羟色胺(5-HT)受体之一。它在中枢神经系统和外周组织中都有发现。该受体参与了多种生理和病理机制。例如，昼夜节律的调节、学习和记忆、温度动态平衡、睡眠调节和神经精神障碍，特别是情绪障碍。近年来，我们对5-HT7受体功能的了解稳步增加。选择性拮抗剂和基因敲除小鼠品系的出现使这一点成为可能。其中一个菌株是由我们产生的，它的使用导致了几个重要的发现。我们已经能够更清楚地描绘5-HT7受体在大脑中的分布，详细描述该受体在5-HT7介导的体温调节中的作用，并发现5-HT7受体在学习和记忆中的作用。药理学和行为学研究表明，5-HT7受体在情感性和精神病性疾病中发挥了作用。我们建议使用动物模型来研究这些假说，这些动物模型已被证明对评估药物治疗抑郁症或精神分裂症的疗效具有预测价值。拟采用的动物模型有强迫游泳实验和尾部悬吊实验来评估抑郁。初步数据显示，在这些测试中，缺乏5-HT7受体的小鼠处于更“抗抑郁”的状态。我们还将研究5-HT7受体在海马神经发生中的作用，这是一种对抑郁症至关重要的现象。对于精神分裂症，将使用具有脉冲前抑制(PPI)的声学惊吓反射。初步数据显示，5-HT7受体基因敲除小鼠不太容易受到药物诱导的PPI中断的影响。这些研究将为可能改进困扰大量人群的疾病的治疗提供有价值的数据。

DESCRIPTION (provided by applicant): The 5-HT7 receptor is one of the more recently discovered receptors for serotonin (5-HT). It is found both in the central nervous system and in peripheral tissues. This receptor has been implicated in many physiological and pathological mechanisms. Examples include regulation of circadian rhythm, learning and memory, temperature homeostasis, sleep regulation, and neuropsychiatric disorders, especially mood disorders. Recent years have shown a steady increase in our knowledge of 5-HT7 receptor function. This has been made possible by the availability of selective antagonists and knockout mice strains. One of these strains was generated by us and its use has led to several important discoveries. We have been able to more clearly map the distribution of 5-HT7 receptors in the brain, describe in detail the role of this receptor in 5-HT-mediated thermoregulation, and discovered a role for the 5-HT7 receptor in learning and memory. Pharmacological and behavioral studies have suggested a role for the 5-HT7 receptor in affective and psychotic diseases. We propose to investigate these hypotheses using animal models that have been shown to have predictive value for assessing the efficacy of drugs in treating depression or schizophrenia. The animal models to be used are the forced swim test and the tail suspension test to evaluate depression. Preliminary data show that mice lacking the 5-HT7 receptor are in a more "anti-depressed" state in these tests. We will also investigate the role of the 5-HT7 receptor in hippocampal neurogenesis, a phenomenon of importance for depression. For schizophrenia the acoustic startle reflex with prepulse inhibition (PPI) will be used. Preliminary data show that 5-HT7 receptor knockout mice are less susceptible to drug-induced disruption of PPI. These studies will provide valuable data for possible improvements of the therapy for disorders that afflicts large groups of the population.