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: 8696817
• 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/8696817
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abstinence; Adolescent; Adolescent and Young Adult; 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.

描述（由申请人提供）： 饮酒定义为将血液酒精含量提高到80 mg％或以上的饮酒一直在增加，而青少年和年轻人的饮酒一直在增加，而这种先前的经验是对饮酒后期的有力预测指标。证据还表明，暴饮暴食是军队中的持续问题，在年轻人进入军队中很普遍，酒精使用障碍或暴饮暴食与退伍军人的健康状况受损和慢性健康问题有关。但是，尽管酒精中毒和饮酒障碍导致了美国退伍军人人口的健康问题，但滥用酗酒的生理机制仍然知之甚少。这部分归因于多个受体和离子通道的酒精作用。与本提案相关，越来越多的证据暗示了活动依赖于谷氨酸能神经传递作为上瘾大脑中的主要基础事件的疗效的变化。这些神经适应机制可能反映了异常脑可塑性的表现，并且已经提出，青少年大脑的增强在时间上与增强的成瘾脆弱性相关。考虑到这一点，目前的提案基于强大的初步数据，表明暴饮暴食会在谷氨酸能系统中产生变化，该数据可以与压力相互作用以增加随后的乙醇饮用行为，并且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暴饮暴食的模型（预定的高酒精消耗，SHAC），发现青少年小鼠的暴饮暴食经验在成年期间显着增加了乙醇的摄入量，在暴露于约束压力后进一步增加。重要的是，青少年比成年人对暴饮暴食对随后摄入量的影响更敏感。通过代谢受体亚型5（MGLUR5）拮抗剂降低了用SHAC程序进行暴饮暴食，并上调了伏隔核（NAC）MGLUR5-HOMER2-HOMER2-HOMER2-磷脂酰氨基素醇3-激酶（PI3K）信号传导。与细胞外谷氨酸水平（通过微透析）和神经末端谷氨酸免疫标记之间的反比关系一致，暴饮暴食的反复出现显着提高了细胞外谷氨酸水平，并降低了神经末端的谷氨酸免疫标记，使神经末端降低了神经末端，从而使不对比（兴奋性）的突触接触。基于这一证据，拟议的研究的目的是检验以下假设：在成年期，暴饮暴食会议赋予增强酒精摄入量后，谷氨酸神经可塑性的适应性。次要假设是，压力会产生额外的适应性，从而进一步增加了饮酒量的脆弱性。拟议的研究将在男性和雌性青少年和成年C57BL/6小鼠中进行，因为我们预测在暴饮暴食和承受压力后发生的谷氨酸能神经适应性的性（青少年）和年龄（青少年>成人）差异。具体目的将使用多学科的方法来确定身体或心理压力源在随后的乙醇摄入量（AIM 1）上是否会产生添加作用（AIM 1），以及谷氨酸免疫标记和树突状脊柱大小和树突状大小和树突状尺寸的变化（AIM 2）以及在谷氨酸基因和信号基因的表达中的变化（AIM 2）（AIM）的变化（AIM）的范围（AIM 3）暴饮暴食。这些研究将确定伏伐酸谷氨酸的改变是否是一种重要的神经生物学机制，它赋予了暴饮暴食和暴露于压力后对酒精依赖的易感性增加。该信息可以指导酒精使用障碍或暴饮暴食的药理治疗策略，这是对我们退伍军人治疗的重要重点领域。