Elucidating the Role of Neuroactive Steroids in Tourette Syndrome

阐明神经活性类固醇在抽动秽语综合征中的作用

基本信息

批准号：
9276513
负责人：
Laura Mosher
金额：
$ 2.89万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276513
关键词：
5 Alpha-Reductase Inhibitor Acute Adolescent Adult Adverse effects Adverse reactions Affect Agonist Allopregnanolone Animal Model Animals Attenuated Brain Chemosensitization Clinical Research Cognitive Corticosterone DARPP Data Development Disease Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine Receptor Dose Enzymes Event Exhibits Finasteride Functional disorder Genetic Gilles de la Tourette syndrome Goals Impairment Injection of therapeutic agent Intervention Knock-out Knockout Mice Lead Loudness Measures Mediating Mediator of activation protein Motor Motor Tics Movement Mus Neurobiology Neurodevelopmental Disorder Neurotransmitters Nucleus Accumbens Operative Surgical Procedures Oxidoreductase Pathogenesis Patients Pharmaceutical Preparations Pharmacology Phosphorylation Plant Roots Plasma Property Quality of life Receptor Activation Receptor Signaling Reflex action Research Resistance Role SK&amp F 82958 Severities Signal Transduction Steroids Stimulus Stress Testing Therapeutic Time Vocal Tics Wild Type Mouse acute stress base behavior test behavioral pharmacology biological adaptation to stress compliance behavior dopamine system enzyme activity indexing innovation insight male mesolimbic system neurobiological mechanism neurochemistry neuropsychiatric disorder neurosteroids neurotransmission new therapeutic target novel novel therapeutics prepulse inhibition prevent psychologic public health relevance receptor expression response restraint stress sensory input sensory stimulus small hairpin RNA social socioeconomics stress reactivity

项目摘要

DESCRIPTION (provided by applicant): Tourette syndrome (TS) is a neurodevelopmental disorder featuring purposeless and repetitive movements defined as tics. Ample research has shown that these manifestations are primarily rooted in perceptual deficits, which are typically exacerbated by stress. The best-characterized perceptual deficit in TS affects sensorimotor gating, the function aimed at filtering salient sensory input from irrelevant external stimuli. In S patients and animal models, gating deficits are measured as a reduction of prepulse inhibition (PPI) of the startle reflex, which consists in the ability of a weak prestimulus to attenuate the startle response elicited by a loud burst. In keeping with the key role of dopamine in TS pathogenesis, PPI is reduced by activation of dopamine D1 receptors in mice. Current therapies for TS are sometimes poorly effective, in that they are aimed at reducing tic severity, rather than the underlying perceptual problems; furthermore, these drugs can lead to severe motor and cognitive problems, which greatly reduce patient compliance. The goal of our research is to understand the neurobiological bases of the perceptual deficits in TS and use this critical information to identify better therapies. To this end, the research of our group has recently identified that the neurosteroid allopregnanolone (AP), and its biosynthetic enzyme 5α-reductase (5αR) may be optimal candidates for the development of novel therapies for TS. Indeed, clinical studies have shown that the prototypical 5αR inhibitor finasteride markedly reduces tic severity in adult TS patients, without causing overt side effects. Furthermore, this drug attenuates the PPI deficits in mice treated with D1 receptor agonists. Notably, AP is a major modulator of stress response and is increased by acute stress; accordingly, we found that restraint stress also disrupted PPI in mice in a time-dependent fashion. Previous studies have shown that neurosteroids may interfere with D1 receptor signaling. Building on this evidence, we hypothesize that: i) stress may disrupt PPI by enhancing 5αR levels and AP synthesis; and ii) the antidopaminergic properties of finasteride in PPI may reflect the reduced synthesis of AP and alterations of D1 receptor signaling. We will test the hypothesis in two aims, using a combination of behavioral, pharmacological, neurochemical and surgical approaches on 5α-reductase knockout or wild-type mice. Our results will help elucidate the neurobiological mechanisms by which neurosteroids may regulate perceptual deficits in TS, and lead to the identification of novel therapeutic targets for this disorder.

描述（由申请人提供）：抽动秽语综合征（TS）是一种神经发育障碍，其特征是无目的和重复性运动，定义为抽动。大量研究表明，这些表现主要源于知觉缺陷，通常会因 TS 的知觉缺陷而加剧。影响感觉运动门控，该功能旨在过滤不相关的外部刺激的显着感觉输入。在 S 患者和动物模型中，门控缺陷被测量为前脉冲抑制的减少。惊吓反射 (PPI)，包括弱刺激前减弱大声爆发引起的惊吓反应的能力，与多巴胺在 TS 发病机制中的关键作用一致，PPI 通过激活多巴胺 D1 受体而降低。目前对 TS 的治疗有时效果不佳，因为它们的目的是减轻抽动的严重程度，而不是减轻抽动的严重程度。潜在的知觉问题；此外，这些药物可能导致严重的运动和认知问题，从而大大降低患者的依从性，我们研究的目标是了解 TS 知觉缺陷的神经生物学基础，并利用这些关键信息来确定更好的治疗方法。为此，我们课题组的研究最近发现，神经类固醇四氢孕酮（AP）及其生物合成酶5α-还原酶（5αR）可能是开发新型药物的最佳候选者。事实上，临床研究表明，典型的 5αR 抑制剂非那雄胺可显着降低成年 TS 患者的抽动严重程度，且不会引起明显的副作用。此外，该药物还可减轻接受 D1 受体激动剂治疗的小鼠的 PPI 缺陷。是应激反应的主要调节剂，并且会因急性应激而增加；因此，我们发现束缚应激也会以时间依赖性方式扰乱小鼠的 PPI。基于这一证据，我们认为：i) 压力可能通过增强 5αR 水平和 AP 合成来破坏 PPI；ii) PPI 中非那雄胺的抗多巴胺能特性可能反映了 AP 合成的减少和 AP 合成的改变。 D1 受体信号传导。我们将在 5α-还原酶敲除小鼠或野生型小鼠上结合使用行为、药理学、神经化学和手术方法来测试这一假设，我们的结果将有助于阐明。神经类固醇可能调节 TS 知觉缺陷的神经生物学机制，并导致确定该疾病的新治疗靶点。