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: 9765124
• 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/9765124
• 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; Exposure to; 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 effect; adolescent alcohol exposure; alcohol exposure; alcohol response; alcohol use disorder; behavior change; behavioral disinhibition; 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（由申请人提供）：这是成年期青少年饮酒神经生物学 (NADIA) 联盟的第四个组成部分。该部分重点关注青少年间歇性乙醇 (AIE) 暴露对睡眠和清醒电生理学以及伴随行为结果的影响的可转化研究。我们已经证明，人类青少年的酗酒会对以事件相关电位和事件相关振荡（ERP/ERO）为索引的清醒电生理学测量产生持续影响。我们实验室的研究还表明，患有酒精使用障碍的年轻人报告了严重的睡眠不足。尽管睡眠障碍在酗酒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。造成这种情况的部分原因是，人类青少年经常患有共病的医学、精神和其他物质使用障碍，以及可能早于饮酒之前的失眠危险因素。了解酒精对青少年睡眠稳态影响的另一个障碍是开发可转化的动物模型，该模型将允许进行必要的控制，以调查青少年酒精暴露对睡眠的长期影响并开发新的治疗方法。过去五年来，我们在大鼠身上证明，通过蒸气产生的 AIE 可以导致 ERP 测量、慢波睡眠、抑制行为受损以及对酒精反应低等变化，直至成年期，与人类状况相似。下面概述的研究将扩展这些研究，并调查 AIE 对行为、睡眠和清醒电生理学有害影响的神经机制。我们目前的假设侧重于两个大脑系统在酒精引起的睡眠/觉醒中断中的重要性：(1) 位于下丘脑外侧角周围 (pLH) 的下丘脑分泌素/食欲素系统和 (2) 位于中位视前区 (MnPO) 的 GABA 能系统。此外，我们认为 AIE 还会延迟与唤醒和奖励相关的调节回路的大脑和行为成熟度，从而导致青少年表型的保留（例如“锁定”），证据如下：对酒精的低反应、对奖励相关刺激的反应改变、行为去抑制和过量饮酒。我们进一步建议，这种不成熟可以通过突触棘的测量来衡量。最后，我们建议测试可能改善 AIE 引起的睡眠/觉醒和行为缺陷的靶向治疗药物。最近被证明可以改善人类酗酒者睡眠障碍的一种药物（加巴喷丁），以及两种针对 Hct/OX 受体的针对酒精引起的失眠的新治疗药物将被研究。概述的研究将确定 AIE 诱发的睡眠病理学的潜在机制，以及使用可转化为人类状况的电生理学措施测试的新疗法。