Neurobiology of Impulsivity and Alcoholism

描述(由申请人提供)：本项目的目的是了解5-羟色胺(5-羟色胺)和多巴胺(DA)神经系统与酒精中毒风险相关的内在差异。被研究的模型，同行饲养的恒河猴，在酒精中毒的临床相关性方面具有显著的表面有效性：脑脊液(CSF)中5-羟色胺代谢物5-羟基吲哚乙酸(5-HIAA)水平降低，对乙醇的摄入量和耐受性增加，行为冲动和攻击性增加。脑脊液5-HIAA降低与冲动和高酒精摄入量相关暗示5-羟色胺功能障碍，但这些功能差异尚不清楚。它们对腹侧纹状体DA的影响也是未知的，后者也与冲动和酒精奖励有关。这项拟议的研究将直接检查5-羟色胺和多巴胺能突触前功能的不同方面，以确定哪些变化与脑脊液5-HIAA减少有关。具体目的是：1)采用体内微透析技术，比较母猴与同龄猕猴前脑5-羟色胺神经支配的突触前活性。基础细胞外浓度的具体评估将在清醒的坐姿动物中使用定量的无净通量方法来确定。5-羟色胺转运体的功能将在相同的研究中通过测定体内5-羟色胺的摄取来评估。2)对母养和同种饲养恒河猴的前脑和脑干内5-羟色胺转运体进行脑成像。我们将使用带有[11C]DASB的microPET方法，[11C]DASB是一种高度选择性的5-羟色胺转运体配体，能够标记前脑部位。成像结果指标将与在Aim 1.3中在相同动物中测定的5-羟色胺转运的功能指标进行比较。使用微透析法比较清醒的母亲饲养的动物和同伴饲养的动物腹侧纹状体DA和皮质5-羟色胺对急性乙醇的反应。4)比较母系和同系饲养动物死后全组织5-羟色胺、5-羟色胺、5-羟色胺转运体、多巴胺及其代谢产物和单胺氧化酶活性的变化。这些数值将通过目标1、2和3中的成像和微透析措施在不同个体之间进行比较。未使用的脑组织将被储存起来，以备将来使用

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