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(申请人提供)：酗酒是美国最普遍的酒精中毒形式，据报道，青少年和年轻人酗酒的比例很高。这是值得关注的，因为青春期/成年期是一个强大的神经发育时期，在此期间，前脑谷氨酸神经元建立了与杏仁核扩大的皮质下结构的连接，杏仁核负责调节情绪性和动机行为。因此，在这一关键时期酗酒很可能严重扰乱杏仁核内谷氨酸系统的发育轨迹，这可能导致情感性和酒精使用障碍的高患病率。事实上，据报道，早期酗酒史极大地促进了人类情感障碍精神症状的出现。与人类的情况一致，酒精天真的雄性和雌性青春期小鼠对压力源反应过度，自愿酗酒，比成年小鼠喝更多的酒。同样与人类的情况一致的是，青春期狂欢饮酒者对早期戒酒产生的“宿醉”相关的焦虑状态不敏感，但他们的应激源反应在长期戒酒过程中孵化。因此，我们假设，在酒精引起的影响情绪的杏仁核神经回路中存在发育差异，这影响了酒精戒断过程中负面情绪的表现。本提案试图使用一种新的、但得到充分验证的小鼠模型来回答一些研究问题，这些问题是关于过度自愿酗酒对情感行为的影响，作为酗酒开始年龄×戒酒持续时间之间相互作用的函数。随着饮酒开始年龄X性互动被报道为情感障碍和酒精使用障碍的共病，Aim 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酗酒诱导的负面情绪的个体发生。这些研究将绘制出戒断诱导的情感变化的表现如何作为一种功能性药物禁欲的变化，潜在地随着生殖周期的变化而变化，并与随后的酗酒有关。目的2将使用免疫印迹程序来确定在酒精戒断诱导的过度焦虑和酗酒的生化相关性中的主观因素的相互作用。然后，目的3将使用行为神经药理学方法来确定酒精戒断引起的杏仁核中央核内谷氨酸神经传递的变化与焦虑和抑郁测量中的主观因素相互作用的功能相关性。这些研究的结果将为青少年酗酒对神经回路中兴奋性神经传递的神经生物学影响提供新的见解，并将确定 这样的变化会导致情感障碍和酒精使用障碍的共病。这些信息不仅将进一步加深我们对过量饮酒调节个体差异的分子机制的理解，而且有助于更深入地了解酒精中毒-情感障碍共病的病因，以指导更有效的治疗。