4/8 NADIA UO1 Effects of Adolescent Alcohol on Drinking, Sleep and Brain Connectivity: Focus on Hypocretin

 描述(由申请人提供)：这是青少年成年饮酒神经生物学(NAIDA)联盟的第四个组成部分。本部分侧重于关于青少年间歇性酒精(AIE)暴露对睡眠和清醒电生理学以及伴随的行为结果的影响的可翻译研究。我们已经证明，在人类青少年中，酗酒对事件相关电位和事件相关振荡(ERP/EROS)指标的清醒电生理指标产生持续的影响。我们实验室的研究也表明，患有酒精使用障碍的年轻人报告了严重的睡眠缺陷。尽管睡眠障碍在酒精中毒的发展中具有明显的重要性，但失眠和酒精依赖之间的复杂关系仍然知之甚少。其部分原因是，人类青少年经常患有共病的医疗、精神和其他物质使用障碍，以及可能在饮酒之前就已失眠的风险因素。在了解酒精对青少年睡眠稳态的影响方面取得进展的另一个障碍是开发可翻译的动物模型，该模型将允许必要的控制，以研究青少年酒精暴露对睡眠的长期影响，并开发新的治疗方法。在过去的五年里，我们已经在大鼠身上证明，通过蒸气的AIE可以产生ERP测量的变化，慢波睡眠，抑制行为的损害，以及对酒精的低反应，直到成年，类似于人类的情况。下面概述的研究将扩展这些研究，并探索AIE对行为、睡眠和清醒电生理学有害影响的神经机制。我们目前的假设集中在两个大脑系统在酒精引起的睡眠/觉醒障碍中的重要性：(1)位于穹隆周围外侧下丘脑(PLH)的下丘脑下丘脑下丘脑下丘脑下丘脑外侧区(PLH)和(2)位于正中视前区(MnPO)的GABA能系统。此外，我们认为，AIE还延迟了与唤醒和奖励相关的调节回路中的大脑和行为成熟，这可能会导致青少年表型的保留(如：对酒精的低反应，对奖励相关刺激的反应改变，行为去抑制和过度饮酒)。我们进一步认为，这种不成熟可以用突触脊椎的测量来衡量。最后，我们建议测试靶向治疗药物，以改善AIE诱导的睡眠/觉醒和行为缺陷。一种最近被证明可以改善人类酗酒者睡眠障碍的药物(加巴喷丁)，以及两种针对Hct/ox受体的治疗酒精引起的失眠的新药将被研究。概述的研究将确定AIE诱导睡眠病理的潜在机制，以及使用可转化为人类条件的电生理措施测试的新疗法。

 DESCRIPTION (provided by applicant): This is the fourth component of the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium. This component has a focus on translatable studies on the effects of Adolescent Intermittent Ethanol (AIE) exposure on sleep and waking electrophysiology and concomitant behavioral outcomes. We have demonstrated that binge drinking in human adolescents produces persistent effects on measures of waking electrophysiology as indexed by event-related potentials and event-related oscillations (ERP/EROs). Studies from our laboratory have also demonstrated that young adults with alcohol use disorders report significant sleep deficits. Despite the clear importance of sleep disturbance in the development of alcoholism the complex relationship between insomnia and alcohol dependence continues to remain poorly understood. The reason for this is, in part, because human adolescents often have co-morbid medical, psychiatric and other substance use disorders, as well as risk factors for insomnia that may have predated their alcohol use. An additional barrier to progress in understanding the impact alcohol has on adolescent sleep homeostasis is the development of translatable animal models that would allow the control necessary to investigate the long term effects of adolescent alcohol exposure on sleep and to develop new therapeutics. Over last five years we have demonstrated in rats that AIE via vapor can produce changes in ERP measures, slow wave sleep, impairments in inhibitory behaviors, and low response to alcohol, well into adulthood, similar to the human condition. The studies outlined below will extend those studies and investigate the neural mechanisms underlying the deleterious effects of AIE on behavior, sleep and waking electrophysiology. Our current hypothesis focuses on the importance of two brain systems in alcohol-induced sleep/wake disruption: (1) the hypocretin/orexin systems located in the perifornical lateral hypothalamus (pLH) and (2) the GABAergic system in the median preoptic (MnPO) region. Additionally, we suggest that AIE also delays brain and behavioral maturity in regulatory circuitry related to arousal and reward that can lead to a retention of the adolescent phenotype (e.g."lock-in") as evidenced by: a low response to alcohol, altered responses to reward related stimuli, behavioral disinhibition and excessive drinking. We further suggest that this immaturity may be indexed by measures of synaptic spines. Finally, we propose to test targeted therapeutic agents that may ameliorate the AIE-induced sleep/wake and behavioral deficits. One that has recently been demonstrated to improve sleep disturbances seen in human alcoholics (gabapentin), as well as two new therapeutic drugs for alcohol-induced insomnia that targets Hct/OX receptors will be studied. The studies outlined will identify the mechanisms underlying AIE induced sleep pathology and new therapeutics tested using electrophysiological measures that are translatable to the human condition.