Neurobiology of Impulsivity and Alcoholism

冲动和酗酒的神经生物学

• 批准号: 6952858
• 负责人: CHARLES W BRADBERRY
• 金额: $ 25.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952858
• 关键词: Macaca mulatta; alcoholism /alcohol abuse; amine oxidase (flavin); behavioral /social science research tag; behavioral genetics; brain imaging /visualization /scanning; dopamine receptor; ethanol; high performance liquid chromatography; impulsive behavior; innervation; mesencephalon; microdialysis; neurotransmitter metabolism; parent offspring interaction; peer group; positron emission tomography; prosencephalon; radiotracer; receptor expression; serotonin receptor; serotonin transporter; socioenvironment

DESCRIPTION (provided by applicant): The aim of this project is to understand inherent differences in serotonin (5-HT) and dopamine (DA) neuronal systems associated with risk for alcoholism. The model to be investigated, the peer-reared rhesus monkey, has significant face validity in terms of clinical correlates of alcoholism: reduced cerobrospinal fluid (CSF) levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), increased consumption of, and tolerance to, ethanol, and increased behavioral impulsivity and aggression. An association of decreased CSF 5-HIAA with impulsivity and high ethanol consumption implicates 5-HT dysfunction, but those functional differences remain unknown. Their impact on ventral striatal DA, also implicated in impulsivity and ethanol reward, are also unknown. The proposed studies will directly examine different aspects of 5-HT and dopaminergic presynaptic function to determine what alterations are associated with reduced CSF 5-HIAA. The specific aims are: 1) Using in-vivo microdialysis, compare the presynaptic activity of the 5-HT innervation of the forebrain in mother reared vs. peer reared rhesus monkeys. Specific assessments of basal extracellular concentration will be determined using the quantitative no-net-flux method in awake, chaired animals. The functionality of the 5-HT transporter will be assessed in the same studies by determining the in-vivo uptake of 5-HT. 2) Conduct brain imaging of the 5-HT transporter in the forebrain and brainstem of mother reared and peer reared rhesus monkeys. We will employ microPET methods with [11C]DASB, a highly selective 5-HT transporter ligand capable of labeling forebrain sites. The imaging outcome measures will be compared with the functional measures of 5-HT transport determined in the same animals in aim 1.3) Compare the responsiveness of ventral striatal DA and cortical 5-HT to acute ethanol using microdialysis in awake mother reared and peer reared animals. 4) Compare post-mortem whole tissue levels 5-HT, 5-HIAA, the 5-HT transporter, DA (and its metabolites), and monoamine oxidase activity in cingulate cortex and ventral striatum of mother reared and peer reared animals. The values will be compared across individuals with the imaging and microdialysis measures from aims 1, 2 and 3. Unused brain tissue will be banked for future potential uses

描述（由申请人提供）：该项目的目的是了解与酒精中毒风险有关的5-羟色胺（5-HT）和多巴胺（DA）神经元系统的内在差异。待研究的模型，在酒精中毒的临床相关性方面具有显着的面部有效性：5-HT代谢物，5-羟基内多乙酸（5- hiaa）的cer骨脊髓液（CSF）水平降低，增加，以及对源化和远洋的影响，并增加了行为和行为和行为和行为和行为和行为，并提高了远离的消费率。 CSF 5-HIAA与冲动性和高乙醇消耗的降低的关联暗示了5-HT功能障碍，但这些功能差异仍然未知。它们对腹侧纹状体DA的影响（也涉及冲动性和乙醇奖励）也是未知的。拟议的研究将直接研究5-HT和多巴胺能的突触前功能的不同方面，以确定与CSF 5-HIAA减少有关的改变。具体目的是：1）使用体内微透析，比较母亲饲养的与同伴饲养的恒河猴在前脑5-HT神经的突触前活性。基础细胞外浓​​度的特定评估将使用醒着的椅子动物中的定量无网络法方法确定。 5-HT转运蛋白的功能将在同一研究中通过确定5-HT的体内摄取来评估。 2）在母亲饲养和同伴饲养的恒河猴的前脑和脑干中进行5-HT转运蛋白的脑成像。我们将使用[11C] DASB（一种高度选择性的5-HT转运蛋白配体，能够标记前脑位点的高度选择性的5-HT转运蛋白配体）。将成像结果度量与在AIM 1.3中确定在同一动物中确定的5-HT转运的功能度量进行比较。将腹侧纹状体DA和皮质5-HT与使用微量透析的腹侧纹状体DA和皮质5-HT与急性乙醇进行比较，并在清醒的母亲饲养和同伴饲养的动物中进行了比较。 4）比较验尸后的全组织水平，5-HIAA，5-HT转运蛋白，DA（及其代谢产物）和单胺氧化酶活性在扣带回皮层和母亲饲养和同伴饲养的动物的皮质和腹侧纹状体中。将对目标1、2和3的成像和微透析度量的个人进行比较。未使用的脑组织将用于未来的潜在用途