Exercise, Serotonin and Anxiety

描述（由申请人提供）：大量证据表明血清素系统可以调节焦虑行为，而焦虑症最常见的药物治疗是针对血清素系统的药物。运动也被证明对焦虑有治疗作用，运动的效果可能是通过改变血清素的功能来调节的。本研究旨在探讨5 -羟色胺能药物对焦虑行为的关键脑区——终纹床核（BNST）的调节作用，以及运动对焦虑的影响是否由终纹床核中的5 -羟色胺变化介导。甲基氯苯哌嗪（mCPP）是一种5-HT2B和5-HT2C受体的激动剂（对5-HT2A受体有一定的亲和力），可增加人类和动物的焦虑症状。在啮齿类动物和灵长类动物的许多范例中，BNST被认为与焦虑介导有关。因此，中脑皮层可能是调节血清素对焦虑影响的重要脑区。单个BNST神经元可以对5-HT产生兴奋和/或抑制反应，mCPP注射到BNST中可能具有焦虑性，因为这种药物选择性地激活了这些神经元的兴奋反应，这在一定程度上是由5-HT2受体家族介导的。与人类的报告一致，我们已经表明，在许多动物的焦虑模型中，自愿运动是抗焦虑的。重要的是，自愿运动减少了mCPP后观察到的焦虑增加。本提案中的研究旨在通过行为学、药理学和电生理学的方法来研究运动保护生物体免受mCPP焦虑效应的机制。在本提案的目的1中，我们将通过测定同样注射到BNST的5-HT受体亚型选择性拮抗剂存在时mCPP行为效应的剂量-反应曲线，研究BNST内mCPP的作用是否由5-HT2A或5-HT2C受体介导。我们还将研究自主运动对bnst内mCPP的剂量-反应曲线的影响。在目标2中，我们将在体外BNST切片上使用全细胞膜片钳技术，以确定自愿运动是否会改变血清素对有利抑制的反应，以及相同的治疗是否会改变外源性应用mCPP的剂量-反应曲线。我们将使用选择性拮抗剂分离mCPP对每种5-HT2受体亚型的影响，以确定自愿运动改变了哪些亚型。预计自愿运动将降低一种或多种5-HT2受体家族亚型的功能。焦虑症影响了大约4000万美国成年人，治疗这些疾病的费用非常昂贵。这项提案中的实验旨在调查运动的机制，运动是一种低成本的药物替代品，也能促进其他形式的健康，减少焦虑。了解这些机制将为焦虑障碍的病因和治疗提供关键的见解。

DESCRIPTION (provided by applicant): Substantial evidence suggests that serotonin systems can modulate anxiety behaviors, and the most common pharmacological treatments for anxiety disorders are drugs that target serotonin systems. Exercise has also been shown to be therapeutic in the treatment of anxiety, and the effects of exercise may be mediated through changes in serotonin functioning. The proposed studies are designed to investigate the modulation of a brain region critical for anxiety behaviors, the bed nucleus of the stria terminalis (BNST), by serotonergic drugs, and whether the effects of exercise on anxiety are mediated by serotonin changes in the BNST. Metachlorophenylpiperazine (mCPP), which is an agonist at 5-HT2B and 5-HT2C receptors (with some affinity at 5-HT2A receptors), increases signs of anxiety in both humans and animals. The BNST has been implicated in mediating anxiety in a number of paradigms in rodents and primates. Therefore, the BNST might an important brain region mediating the effects of serotonergic modulation on anxiety. Single BNST neurons can respond to 5-HT with excitation and/or inhibition, and mCPP injected into the BNST is anxiogenic likely because this drug selectively activates the excitatory response on these neurons, which is mediated, in part, by the 5-HT2 family of receptors. Consistent with reports in humans, we have shown that voluntary exercise is anxiolytic in many anxiety models in animals. Importantly, voluntary exercise reduces the increases in anxiety observed after mCPP. The studies in this proposal are designed to investigate the mechanisms by which exercise protects organisms against the anxiogenic effects of mCPP, using behavioral, pharmacological, and electrophysiological methods. In Aim 1 of this proposal, we will investigate whether the effects of intra-BNST mCPP are mediated by 5-HT2A or 5-HT2C receptors by determining the dose-response curves of mCPP's behavioral effects in the presence of 5-HT receptor subtype selective antagonists, also injected into the BNST. We will also then investigate the effects of voluntary exercise on the dose-response curve of intra-BNST mCPP. In Aim 2, we will use whole-cell patch clamp techniques on BNST slices in vitro, to determine whether voluntary exercise shifts the population of serotonin responses to the favor inhibition, and whether the same treatment alters the dose-response curve to exogenously applied mCPP. We will use selective antagonists to isolate the effects of mCPP to each 5-HT2 receptor subtype, to determine which subtype(s) is/are altered by voluntary exercise. It is expected that voluntary exercise will decrease the function of one or more of the subtypes of the 5-HT2 family of receptors. Anxiety disorders affect approximately 40 million American adults and the treatment of these disorders is extremely expensive. The experiments in this proposal are designed to investigate the mechanisms by which exercise, a low-cost alternative to drugs that also promotes other forms of health, reduces anxiety. Understanding these mechanisms will provide critical insight for both the etiology and treatment of anxiety disorders.