Adolescent Alcohol and Anxiety

青少年酒精与焦虑

• 批准号: 9056326
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-03 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056326
• 关键词: Address; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affect; Affective; Affective Symptoms; Age; Age of Onset; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Cell Nucleus; Characteristics; Clinical; Comorbidity; Development; Disease; Emotional; Emotional Disturbance; Etiology; Exhibits; Exposure to; Female; Female Adolescents; Glutamate Receptor; Glutamates; Growth; Heavy Drinking; High Prevalence; Human; Image; Immunoblotting; Incubated; Individual; Individual Differences; Knowledge; Life; Life Experience; Link; Male Adolescents; Measures; Mental Depression; Molecular; Mood Disorders; Mus; Neurobiology; Neuronal Plasticity; Neurons; Pharmacotherapy; Prevalence; Procedures; Prosencephalon; Receptor Signaling; Recording of previous events; Reporting; Research; Role; Severities; Severity of illness; Signaling Molecule; Structure; System; Testing; United States; Withdrawal; Work; adolescent alcohol; adolescent binge drinking; alcohol abstinence; alcohol exposure; alcohol use disorder; binge drinker; binge drinking; clinically relevant; critical period; depressive symptoms; drinking; drinking onset; drug abstinence; effective therapy; emerging adult; indexing; insight; male; motivated behavior; mouse model; negative affect; neural circuit; neuroadaptation; neurodevelopment; neuropsychiatry; neurotransmission; novel; psychiatric symptom; public health relevance; relating to nervous system; reproductive; sex; stressor; transmission process

 DESCRIPTION (provided by applicant): Binge alcohol drinking is the most prevalent form of alcoholism in the United States, with high rates of binge drinking reported in adolescents and young adults. This is concerning as adolescence/early adulthood is a period of robust neurodevelopment during which forebrain glutamate neurons establish their connectivity with subcortical structures within the extended amygdala that regulate emotionality and motivated behavior. Thus, binge drinking during this critical period is likely to grossly perturb the developmental trajectories of glutamate systems within the extended amygdala, which may contribute to the high prevalence of comorbid affective and alcohol use disorders. Indeed, an early history of alcohol abuse is reported to advance significantly the onset of psychiatric symptoms of affective disorders in humans. Consistent with the human condition, alcohol-naïve male and female adolescent mice are hyper-reactive to stressors and voluntarily binge drink greater amounts of alcohol, than their adult counterparts. Also consistent with the human condition, adolescent-onset binge drinkers are insensitive to the "hang-over"-related anxiogenic state produced by early alcohol withdrawal, but their stressor reactivity incubates during protracted withdrawal. Thus, it is hypothesized that developmental differences exist in alcohol-induced perturbations within the extended amygdala neural circuitry underpinning emotionality, which impact the manifestation of negative affect during alcohol withdrawal. The present proposal seeks to answer a number of research questions pertaining to the impact of excessive voluntary binge alcohol intake on affective behavior as a function of the interactions between age of binge drinking onset X duration of alcohol abstinence using a novel, but well-validated, murine model. As age of drinking onset X sex interactions are reported for affective and alcohol use disorder comorbidity, Aim 1 will carefully control early life experiences and alcohol exposure to characterize the ontogeny of binge drinking-induced negative affect in both male and female subjects. These studies will chart how the manifestation of withdrawal-induced changes in affect vary as a function drug abstinence, potentially vary with reproductive cycle and relate to subsequent binge drinking. Aim 2 will employ immunoblotting procedures to identify subject factor interactions in the biochemical correlates of alcohol withdrawal-induced hyper-anxiety and binge drinking. Aim 3 will then employ behavioral neuropharmacological approaches to determine the functional relevance of alcohol withdrawal- induced changes in glutamate neurotransmission within the central nucleus of the amygdala for subject factor interactions in anxiety and depression measures. The results of these studies will provide novel insight into the neurobiological impact of adolescent binge drinking upon excitatory neurotransmission within a neural circuit critical for emotionality and motivated behavior and will determine the relevance of such changes for affective and alcohol use disorder comorbidity. Such information will not only further our understanding of the molecular mechanisms regulating individual differences in excessive alcohol intake, but provide greater insight into the etiology of alcoholism-affective disorder comorbidity to direct more effective treatment.

 描述（由申请人提供）：酗酒是美国最普遍的酒精中毒形式，青少年和年轻人中酗酒率很高。这是因为青春期/成年早期是一个强大的神经发育时期，在此期间，前脑谷氨酸神经元与扩展杏仁核内的皮质下结构建立连接，调节情绪和动机行为。因此，在这一关键时期，酗酒可能会严重扰乱扩展杏仁核内谷氨酸系统的发育轨迹，这可能导致情感和酒精使用障碍共病的高患病率。事实上，据报道，早期的酒精滥用史会显著提前人类情感障碍的精神症状的发作。与人类的情况一致，酒精幼稚的雄性和雌性青春期小鼠对压力源反应过度，并且比成年小鼠自愿狂饮更多的酒精。同样与人类的情况相一致的是，醉酒发作的酗酒者对早期戒酒产生的“宿醉”相关的焦虑状态不敏感，但他们的应激反应在长期戒断过程中潜伏。因此，据推测，发展差异存在于酒精诱导的扰动内扩展杏仁核神经回路的基础情绪，影响的表现，酒精戒断过程中的负面影响。目前的建议旨在回答一些研究问题有关的影响，过量的自愿酗酒的情感行为作为一个功能之间的相互作用的酗酒发病年龄X戒酒时间使用一种新的，但经过充分验证的，鼠模型。由于报告了情感和酒精使用障碍合并症的饮酒起始年龄X性别相互作用，目标1将仔细控制早期生活经历和酒精暴露，以表征男性和女性受试者中狂欢饮酒诱导的负面影响的个体发生。这些研究将描绘出戒断引起的情感变化的表现如何随着药物戒断的功能而变化，可能随着生殖周期而变化，并与随后的酗酒有关。目的2将采用免疫印迹程序，以确定主题因素的相互作用，在生化相关的酒精戒断引起的过度焦虑和酗酒。目标3将采用行为神经药理学方法，以确定功能相关的酒精戒断诱导的变化，谷氨酸神经传递的中央核杏仁核的主题因素的相互作用，焦虑和抑郁的措施。这些研究的结果将为青少年酗酒对神经回路内兴奋性神经传递的神经生物学影响提供新的见解，这些神经回路对情绪和动机行为至关重要，并将确定青少年酗酒与神经系统的相关性。 这些变化是情感障碍和酒精使用障碍的共病。这些信息不仅将进一步我们的分子机制，调节个体差异，过量饮酒的理解，但提供了更深入的了解酒精中毒情感障碍共病的病因，以指导更有效的治疗。