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

4/8 NADIA UO1 青少年酒精对饮酒、睡眠和大脑连接的影响：关注下丘脑分泌素

• 批准号: 9326105
• 负责人: CINDY L EHLERS
• 金额: $ 40万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326105
• 关键词: Adolescent; Adult; Affective; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Anxiety; Arousal; Auditory; Behavior; Behavioral; Brain; Chronic; Collaborations; Complex; Deltastab; Dendritic Spines; Development; Disinhibition; Dose; Electrophysiology (science); Epigenetic Process; Ethanol; Event; Event-Related Potentials; Female; Heavy Drinking; Hematocrit procedure; Hippocampus (Brain); Homeostasis; Human; Hypothalamic structure; Immunohistochemistry; Impairment; Laboratories; Lateral; Lead; Long-Term Effects; Marble; Measures; Mediating; Medical; Modeling; Neurobiology; Neuroimmune; Neurons; Pathology; Pharmaceutical Preparations; Phenotype; Preoptic Areas; Rattus; Reporting; Rewards; Risk Factors; SB-334867; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Slow-Wave Sleep; Stimulus; Substance Use Disorder; Swimming; Synapses; System; Testing; Therapeutic Agents; Vertebral column; adolescent alcohol; adolescent alcohol exposure; alcohol exposure; alcohol response; alcohol use disorder; behavior change; behavioral outcome; binge drinking; drinking; gabapentin; gamma-Aminobutyric Acid; hypocretin; improved; indexing; male; neurochemistry; neuromechanism; neurophysiology; novel therapeutics; problem drinker; public health relevance; receptor; response; targeted treatment; therapeutic evaluation; underage drinking; vapor; young adult

 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.

 描述（由适用提供）：这是青少年饮酒（NADIA）财团神经生物学的第四个组成部分。该组成部分专注于对青少年间歇性乙醇（AIE）暴露对睡眠和唤醒电生理学和伴随行为结果的影响的影响。我们已经证明，人类青少年饮料对醒来的电生理学的度量产生持续的影响，因为事件相关电位和与事件相关的振荡（ERP/EROS）索引。我们实验室的研究还表明，患有饮酒障碍的年轻人报告了大量睡眠定义。尽管睡眠灾难在酗酒的发展中显而易见，但失眠与酒精依赖之间的复杂关系仍然保持不足。原因部分是因为人类青少年经常患有医学，精神病和其他药物使用障碍，以及可能已任命其饮酒的失眠症的危险因素。了解酒精对青少年睡眠体内稳态影响的进展的另一个障碍是可翻译动物模型的发展，该模型将允许控制青少年酒精暴露对睡眠的长期影响并开发新疗法的长期影响。在过去的五年中，我们在大鼠中证明，通过蒸气的AIE可以在ERP测量，慢波睡眠，抑制行为的障碍和对酒精的反应中产生变化，直到成年，类似于人类状况。下面概述的研究将扩展这些研究，并研究AIE对行为，睡眠和清醒电生理学的有害影响的神经元机制。我们目前的假设着重于两个大脑系统在酒精引起的睡眠/唤醒破坏中的重要性：（1）位于perifornical侧侧下丘脑（PLH）和（2）中间preptic（MNPO）区域中的GABA能系统中的低载素/甲状腺素系统。此外，我们建议AIE还延迟了与唤醒和奖励有关的调节电路中的大脑和行为成熟度，这可能导致对青少年表型的保留（例如“锁定”），这证明了对酒精的反应低，对奖励相关刺激的反应改变，行为抑制了双重抑制，饮酒和过量饮酒。我们进一步建议，这种不成熟可能是通过突触刺的度量来索引的。最后，我们建议测试可能改善AIE引起的睡眠/唤醒和行为定义的靶向治疗剂。最近已证明一种可以改善人类酒精中毒（Gabapentin）的睡眠障碍，以及两种用于酒精引起的失眠症的新治疗药物，该药物将研究HCT/OX受体。概述的研究将确定AIE诱导的睡眠病理学基础的机制和使用可转换为人类状况的电生理测量测试的新疗法。