Adolescent Binge Drinking Increases Adult Alcohol Intake: Glutamate Mechanisms

青少年酗酒会增加成人酒精摄入量：谷氨酸机制

• 批准号: 8140726
• 负责人: DEBORAH A. FINN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140726
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abstinence; Adolescent; Adult; Affect; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Area; Behavioral; Biological; Blood alcohol level measurement; Brain; C57BL/6 Mouse; Chronic; Clinical; Complex; Consumption; Corticosterone; Cytoskeleton; Data; Dendritic Spines; Dependence; Development; Disease; Electron Microscopy; Ethanol; Event; Exposure to; Female; Female Adolescents; Gene Expression; Gene Expression Profile; Genes; Glutamates; Goals; Health; Health Status; Healthcare; Homeostasis; Immediate-Early Genes; Impaired health; Impairment; Intake; Ion Channel; Label; Laboratories; Letters; Life; Male Adolescents; Measurement; Measures; Mediating; Metabotropic Glutamate Receptors; Microdialysis; Military Personnel; Mind; Mission; Modeling; Molecular; Mus; Nerve; Neuronal Plasticity; Neurosciences; Neurotransmitters; Nucleus Accumbens; Odors; Olives - dietary; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Phosphorylation; Physiological; Population; Pre-Clinical Model; Predisposition; Prefrontal Cortex; Procedures; Proteins; Publications; Rattus; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Schedule; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Sirolimus; Staging; Stress; Synapses; Synaptic plasticity; System; Testing; Time; United States; Up-Regulation; Veterans; Water; addiction; adolescent binge drinking; alcohol exposure; alcohol reinforcement; alcohol use disorder; alcoholism therapy; base; binge drinking; drinking; drinking behavior; drug seeking behavior; experience; extracellular; human FRAP1 protein; information gathering; information processing; interdisciplinary approach; male; neuroadaptation; neurobiological mechanism; neurochemistry; neurotransmission; novel; preference; problem drinker; psychological stressor; receptor; response; restraint; restraint stress; sex; stressor; transmission process; treatment strategy; young adult

DESCRIPTION (provided by applicant): Binge drinking, defined as drinking that brings blood alcohol levels to 80 mg% or above, has been increasing in adolescents and young adults, and this prior experience is a strong predictor of alcoholic dependence later in life. Evidence also indicates that binge drinking is a persistent problem in the military and is prevalent among young adults entering the military, and that alcohol use disorder or binge drinking are associated with impaired health status and chronic health problems in veterans. However, while alcoholism and alcohol use disorder contribute to health problems in the US veteran population, the physiological mechanisms underlying alcohol abuse remain poorly understood. This is due in part, to alcohol's actions at multiple receptors and ion channels. Relevant to the present proposal, increasing evidence implicates activity dependent changes in the efficacy of glutamatergic neurotransmission as a major underlying event in the addicted brain. These neuroadaptive mechanisms may reflect manifestations of aberrant brain plasticity, and it has been suggested that the enhanced plasticity of the adolescent brain temporally correlates with enhanced vulnerability to addiction. With this in mind, the present proposal is based on strong preliminary data suggesting that binge drinking produces alterations in the glutamatergic system that can interact with stress to augment subsequent ethanol drinking behavior, and that adolescent mice may be more susceptible than adult mice to the impact of these perturbations. We have developed a model of binge drinking (Scheduled High Alcohol Consumption, SHAC) and found that binge drinking experience in adolescent mice significantly increased ethanol intake during adulthood, with further increases following exposure to restraint stress. Importantly, adolescents were more sensitive than adults to the impact of binge drinking on subsequent intake. Binge drinking with the SHAC procedure was decreased by a metabotropic receptor subtype 5 (mGluR5) antagonist, and it upregulated nucleus accumbens (NAc) mGluR5-Homer2-phosphatidylinositol 3-kinase (PI3K) signaling. Consistent with the inverse relationship between extracellular glutamate levels (via microdialysis) and nerve terminal glutamate immunolabelling, repeated bouts of binge drinking significantly increased extracellular glutamate levels and decreased glutamate immunolabelling within nerve terminals making asymmetrical (excitatory) synaptic contacts. Based on this evidence, the goal of the proposed studies is to test the hypothesis that adaptations in glutamate neuroplasticity following binge drinking confer susceptibility for enhanced alcohol intake in adolescent mice during adulthood. A secondary hypothesis is that stress produces additional adaptations that bestow further vulnerability for increased alcohol consumption. The proposed studies will be conducted in male and female adolescent and adult C57BL/6 mice, since we predict that there will be sex (female > male) and age (adolescent > adult) differences in the glutamatergic neuroadaptations that occur following binge drinking and exposure to stress. The specific aims will use a multidisciplinary approach to determine whether physical or psychological stressors will have an additive effect with binge drinking on subsequent ethanol intake (Aim 1), and whether alterations in glutamate immunolabelling and dendritic spine size (Aim 2) as well as alterations in the expression of glutamatergic genes and signaling pathways (Aim 3) within the NAc correspond to the escalation in ethanol intake following stress and binge drinking. These studies will determine whether alterations in accumbal glutamate are an important neurobiological mechanism that confers increased susceptibility for alcohol dependence following binge drinking and exposure to stress. This information can guide pharmacological treatment strategies for alcohol use disorder or binge drinking, an important area of focus in the treatment of our veterans. PUBLIC HEALTH RELEVANCE: Alcoholism is a clinical problem of great significance that is relevant to the VA Mission and that represents a targeted area of VA research. Equally important, binge drinking appears to be a persistent problem in the military, it is prevalent among young adults entering the military, and binge drinking experience is a strong predictor of alcoholic dependence later in life. Given that impaired health status and chronic health problems also are associated with alcohol use disorder and binge drinking, the continuing high rates of alcohol abuse among military personnel and veterans pose a major healthcare dilemma for the Department of Veterans Affairs. The proposed studies will determine whether adaptations in the neurotransmitter glutamate confer increased susceptibility for alcohol dependence following binge drinking and exposure to stress. This information can guide the development of new pharmacological strategies that can be used to reduce binge consumption and the transition to dependence, an important area of focus in the treatment of our veterans.

描述（由申请人提供）： 酗酒，定义为使血液酒精含量达到80 mg%或以上的饮酒，在青少年和年轻人中一直在增加，这种先前的经历是日后生活中酒精依赖的强有力预测因素。证据还表明，酗酒在军队中是一个持续存在的问题，在进入军队的年轻人中很普遍，酒精使用障碍或酗酒与退伍军人的健康状况受损和慢性健康问题有关。然而，虽然酒精中毒和酒精使用障碍导致美国退伍军人的健康问题，但对酒精滥用的生理机制仍然知之甚少。这部分是由于酒精对多种受体和离子通道的作用。与本建议相关的是，越来越多的证据表明，成瘾性大脑中的主要潜在事件是多巴胺能神经传递功效的活动依赖性变化。这些神经适应机制可能反映了异常的大脑可塑性的表现，并且已经表明青少年大脑的可塑性增强与成瘾的脆弱性增强在时间上相关。考虑到这一点，目前的建议是基于强有力的初步数据表明，暴饮暴食产生的变化，可以与压力相互作用，以增加随后的乙醇饮酒行为，青少年小鼠可能比成年小鼠更容易受到这些扰动的影响。 我们已经开发了一种酗酒模型（预定的高酒精消费，SHAC），发现青春期小鼠的酗酒经历显着增加了成年期的乙醇摄入量，并在暴露于约束压力后进一步增加。重要的是，青少年比成年人更敏感的影响，酗酒对随后的摄入量。代谢型受体亚型5（mGluR 5）拮抗剂可减少SHAC程序中的酗酒，并上调丘脑核（NAc）mGluR 5-Homer 2-磷脂酰肌醇3-激酶（PI 3 K）信号转导。与细胞外谷氨酸水平（通过微透析）和神经末梢谷氨酸免疫标记之间的反比关系一致，反复发作的暴饮暴食显着增加细胞外谷氨酸水平和减少神经末梢内的谷氨酸免疫标记，使不对称（兴奋性）突触接触。基于这一证据，拟议研究的目标是检验这样的假设：酗酒后谷氨酸神经可塑性的适应赋予青春期小鼠成年期酒精摄入量增加的易感性。第二个假设是，压力产生额外的适应，使更多的脆弱性增加酒精消费。拟议的研究将在雄性和雌性青少年和成年C57 BL/6小鼠中进行，因为我们预测在酗酒和暴露于压力后发生的兴奋性神经适应中将存在性别（雌性>雄性）和年龄（青少年>成年）差异。具体目标将使用多学科方法来确定身体或心理压力源是否会与酗酒对随后的乙醇摄入量产生叠加效应（目标1），以及谷氨酸免疫标记和树突棘大小（Aim 2）的改变以及谷氨酸能基因表达和信号通路（Aim 3）的改变是否与在NAc内，对应于压力和酗酒后乙醇摄入量的增加。这些研究将确定谷氨酸盐的改变是否是一种重要的神经生物学机制，这种机制使酗酒和暴露于压力后对酒精依赖的易感性增加。这些信息可以指导酒精使用障碍或酗酒的药物治疗策略，这是我们退伍军人治疗的一个重要领域。 公共卫生关系： 酒精中毒是一个具有重要意义的临床问题，与VA使命相关，代表VA研究的目标领域。同样重要的是，酗酒似乎是军队中一个持续存在的问题，它在进入军队的年轻人中很普遍，酗酒经历是以后生活中酒精依赖的一个强有力的预测因素。鉴于健康状况受损和慢性健康问题也与酒精使用障碍和酗酒有关，军事人员和退伍军人中酒精滥用的持续高比率给退伍军人事务部带来了重大的医疗困境。拟议中的研究将确定神经递质谷氨酸的适应是否会增加酗酒和暴露于压力后对酒精依赖的易感性。这些信息可以指导新的药理学策略的开发，这些策略可用于减少暴饮暴食和向依赖性的过渡，这是我们退伍军人治疗的一个重要重点领域。