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.