The amygdaloid 5-HT2C receptor in anxiety-like behavior

描述(申请人提供)：焦虑症是美国最常见的心理健康问题之一。它还伴随着其他情感障碍，如抑郁症。焦虑症的病因仍不清楚，可能很复杂。此外，目前的治疗方法存在严重缺陷。因此，有必要研究焦虑症的病因，开发更好的治疗焦虑症的方法。5-羟色胺2c(5-HT2C)受体在调节焦虑行为中发挥作用。来自人类和啮齿动物的研究表明，激活5-HT2C受体会产生一种焦虑效应。惊恐障碍患者对5-HT2C受体的敏感性增加。相反，5-HT2C受体拮抗剂具有抗焦虑作用。然而，关于5-HT2C受体调节焦虑行为的神经回路和细胞和分子机制知之甚少。目前应用的目的是确定杏仁核5-HT2C受体在调节焦虑样行为中的作用。我们的假设是杏仁核中的5-HT2C受体在焦虑样行为的调节中起着重要作用。杏仁核被称为恐惧中心，它含有高密度的5-HT2C受体。我们最近发现，5-羟色胺转运体基因敲除的小鼠表现出更多的焦虑样行为，并且这些小鼠的杏仁核中5-HT2C受体的密度增加。为了验证这一假设，我们将追求两个具体目标：1)我们将鉴定含有5-HT2C正义和反义序列的重组腺病毒，以便它们可以用于操纵5-HT2C受体的表达；2)我们将确定杏仁核中5-HT2C受体对焦虑样行为的影响。动物的焦虑行为将通过高架加迷宫、开阔场地和恐惧条件反射测试进行评估。这些研究结果将为5-HT2C受体参与焦虑行为调控的定位提供第一线证据，为进一步研究5-HT2C受体参与焦虑行为调控的神经元回路及细胞和分子机制奠定基础。此外，拟议的研究很有可能导致开发治疗焦虑症的新药。

DESCRIPTION (provided by applicant): Anxiety disorder is one of the most common mental health problems in the United States. It also accompanies with other affective disorders such as depression. The etiology for anxiety disorders is still unknown and may be complicated. Furthermore, current therapeutic approaches suffer from serious deficiencies. Therefore, it is essential to study the etiology of anxiety disorders and develop better therapeutic approaches for anxiety disorders. Serotonin2c (5- HT2c) receptors play a role in the regulation of anxiety behaviors. Studies, from both humans and rodents, indicate that activation of 5-HT2c receptors produces an anxiogenic effect. Increased sensitivity of 5-HT2c receptors was found in patients with panic disorder. Conversely, 5-HT2c receptor antagonists produce anxiolytic effect. However, little is known regarding the neural circuitry and the cellular and molecular mechanisms that mediate the effect of 5-HT2c receptors on the regulation of anxiety behaviors. The objective of the current application is to determine the role of amygdaloid 5-HT2c receptors in the regulation of anxiety-like behaviors. Our hypothesis is that 5-HT2c receptors in the amygdala play an important role in the regulation of anxiety-like behaviors. The amygdala is known as a fear center and it contains a high density of 5-HT2c receptors. We recently found that serotonin transporter knockout mice show increased anxiety-like behaviors and that the density of 5-HT2c receptors is increased in the amygdala of these mice. To test the hypothesis, we will pursue 2 specific aims: 1) We will characterize recombinant adenovirus containing 5-HT2c sense and antisense sequences, so that they can be used to manipulate the expression of 5-HT2c receptors; and 2) We will determine the effect of 5-HT2c receptors in the amygdala on anxiety-like behaviors. Anxiety like behavior of the animals will be assessed by elevated plus maze, open field and fear conditioning tests. The outcome of the studies will be the first line of evidence for the location of 5-HT2c receptors that are involved in the regulation of anxiety behavior, which will be the foundation for the future studies on the neuronal circuitries and the cellular and molecular mechanisms mediating 5-HT2c receptor-involved regulation of anxiety behaviors. Furthermore, the proposed studies have a high potential of leading to the development of novel drugs to treat anxiety disorders.