Neurobiological studies of gammahydroxybutyrate

性状（由申请方提供）：γ-羟基丁酸（GHB）是一种中间代谢产物，对中枢神经系统（CNS）的活动，特别是对意识有深远影响。由于其催眠作用，GHB已成为一种滥用药物，矛盾的是，它也是治疗睡眠障碍发作性睡病的临床有效治疗药物。发作性睡病是一种快速眼动（REM）睡眠相关的疾病，大约每1000个美国人中就有1人患有这种疾病，其特征是白天过度嗜睡（EDS），cataepsy（由情绪刺激引发的肌肉张力突然丧失）和一系列其他症状。Xyrem是GHB的钠盐，已被美国食品和药物管理局批准用于治疗发作性睡病的cataeprazole和EDS症状。GHB促进EEG和慢波睡眠（SWS）中的慢波活动（SWA），从而巩固夜间睡眠并导致第二天的警觉性增加。尽管其临床用途，GHB的作用机制仍然存在争议，有证据表明GHB通过GABA-B受体和中枢神经系统中的特定GHB结合位点发挥作用。本项目的具体目标是确定GHB诱导的SWA的神经底物，并了解GHB对发作性睡病/癫痫的治疗作用的机制。为了实现这些目标，我们将利用一个小鼠模型的发作性睡病/cataeprazole中的下丘脑泌素（Hcrt）神经元退化产后，因为他们在人类发作性睡病。我们将使用这些hcrt/ataxin-3小鼠对我们的初步结果进行随访，这些结果表明GHB可以像在人类中一样减少癫痫样症状，并测试这些治疗效果是通过GABA-B受体介导的假设。我们将进行功能性神经解剖学研究，以检验GHB差异影响hcrt/共济失调蛋白-3小鼠的行为状态调节区的假设。基于我们的初步研究结果，其中GHB诱导Fos的表达在蓝斑（LC），我们将使用神经毒素DSP-4病变去甲肾上腺素能细胞来测试的假设，一个完整的LC是必要的GHB的治疗效果。我们还将进行细胞电生理学研究，以确定是否在LC或腹外侧视前区（VLPO）的神经元的内在特性受到急性或慢性暴露于GHB。最后，我们将评估GHB的治疗效果是否与脑基因表达变化相关。上述研究的结果将提高我们对伽马-羟丁酸治疗活性的神经生物学基础的理解，也可能提供对catabolic和EEG SWA基础的细胞和分子机制的见解。公共卫生相关性在发作性睡病患者中，已观察到以日间过度嗜睡和相关症状为特征的睡眠障碍，脑中下丘脑泌素（Hcrt）神经元变性。γ-羟基丁酸盐（GHB）是一种临床上有用的治疗睡眠障碍发作性睡病的药物，但其作用机制尚不清楚。我们将利用小鼠发作性睡病模型，其中Hcrt神经元在出生后退化，因为他们在人类发作性睡病，以了解GHB是如何有益于人类发作性睡病。

DESCRIPTION (provided by applicant): Gammahydroxybutyrate (GHB), a product of intermediary metabolism, has profound effects on the activity of the central nervous system (CNS), particularly on consciousness. Because of its soporific effects, GHB has become both a drug of abuse and, paradoxically, a clinically useful therapeutic for treatment of the sleep disorder narcolepsy. Narcolepsy, a Rapid Eye Movement (REM) sleep-related disorder that afflicts approximately 1 in 1000 Americans, is characterized by excessive daytime sleepiness (EDS), cataplexy (a sudden loss of muscle tone triggered by emotional stimulation), and a cluster of other symptoms. Xyrem, the sodium salt of GHB, has been approved by the U.S. Food and Drug Administration for the treatment of both the cataplexy and EDS symptoms of narcolepsy. GHB facilitates slow wave activity (SWA) in the EEG and slow wave sleep (SWS), thereby consolidating nocturnal sleep and resulting in increased alertness on the subsequent day. Despite its clinical utility, the mechanism of action of GHB remains controversial with evidence for action both through GABA-B receptors and through specific GHB binding sites in the CNS. The specific goals of this project are to identify the neural substrates of GHB-induced SWA and understand the mechanism(s) underlying the therapeutic effects of GHB on narcolepsy/cataplexy. To achieve these goals, we will exploit a mouse model of narcolepsy/cataplexy in which the hypocretin (Hcrt) neurons degenerate postnatally as they do in human narcoleptics. We will follow up on our preliminary results using these hcrt/ataxin-3 mice which indicate that GHB can reduce cataplexy-like symptoms as it does in humans and test the hypothesis that these therapeutic effects are mediated through the GABA-B receptor. We will conduct functional neuroanatomical studies to test the hypothesis that GHB differentially affects behavioral state regulatory regions in hcrt/ataxin-3 mice. Based on our preliminary results in which GHB induces Fos expression in the locus coeruleus (LC), we will use the neurotoxin DSP-4 to lesion noradrenergic cells to test the hypothesis that an intact LC is necessary for the therapeutic effect of GHB. We will also conduct cellular electrophysiological studies to determine whether the intrinsic properties of the neurons in the LC or the ventrolateral preoptic area (VLPO) are affected by acute or chronic exposure to GHB. Lastly, we will evaluate whether the therapeutic efficacy of GHB is associated with brain gene expression changes. The results of the studies proposed above will enhance our understanding of the neurobiology that underlies the therapeutic activity of GHB and may also provide insights into the cellular and molecular mechanisms that underlie cataplexy and EEG SWA. PUBLIC HEALTH RELEVANCE In patients with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and related symptoms, degeneration of hypocretin (Hcrt) neurons in the brain has been observed. Gammahydroxybutyrate (GHB) is a clinically useful therapeutic for treatment of the sleep disorder narcolepsy but the mechanism of action is unknown. We will exploit a mouse model of narcolepsy in which the Hcrt neurons degenerate postnatally as they do in human narcoleptics to understand how GHB is beneficial in human narcolepsy.