Adolescent Alcohol and Anxiety

青少年酒精与焦虑

基本信息

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
项目类别：
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

项目摘要

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酗酒形式，青少年和年轻人的酗酒率很高，这一点令人担忧，因为青春期/成年早期是神经发育旺盛的时期。前脑谷氨酸神经元与扩展杏仁核内的皮层下结构建立连接，调节情绪和动机行为，因此，在这个关键时期酗酒可能会严重干扰发育。扩展杏仁核内谷氨酸系统的轨迹，这可能导致情感障碍和酒精使用障碍的高患病率。事实上，据报道，早期酗酒史会显着促进人类情感障碍的精神症状的发生。与人类的情况一样，未接触酒精的雄性和雌性青春期小鼠对压力源反应过度，并且会比成年小鼠自愿暴饮更多的酒精。这也与人类的情况一致，青少年发作的暴饮暴食。饮酒者对早期戒酒产生的与“宿醉”相关的焦虑状态不敏感，但他们的应激反应在长期戒酒过程中会潜伏，因此，人们发现，酒精引起的杏仁核神经回路基础扰动存在发育差异。情绪性，这会影响戒酒过程中负面情绪的表现，本提案旨在回答一些与过量自愿饮酒对情感行为的影响有关的研究问题，作为两者之间相互作用的函数。使用新颖但经过充分验证的小鼠模型，酗酒开始的年龄 X 戒酒的持续时间由于饮酒开始的年龄 X 性别相互作用报告了情感和酒精使用障碍合并症，目标 1 将仔细控制早期生活经历和酒精。这些研究将描绘出戒断引起的情感变化的表现如何随功能药物戒断而变化，可能随生殖周期而变化，并与随后的关系相关。目标 2 将采用免疫印迹程序来确定酒精戒断引起的过度焦虑的生化相关性中的受试者因素相互作用，然后目标 3 将采用行为神经药理学方法来确定酒精戒断引起的变化的功能相关性。杏仁核中央核内的谷氨酸神经传递在焦虑和抑郁测量中的主体因素相互作用中这些研究的结果将为青少年酗酒对兴奋性的神经生物学影响提供新的见解。神经回路内的神经传递对于情绪和动机行为至关重要，并将决定情感性酒精和使用障碍合并症的此类变化这些信息不仅将进一步加深我们对调节过量饮酒的个体差异的分子机制的理解，而且可以更深入地了解酒精中毒-情感性障碍合并症的病因学，以指导更有效的治疗。