Neurobiology of Impulsivity and Alcoholism

描述（由申请人提供）：该项目的目的是了解与酒精中毒风险相关的血清素（5-HT）和多巴胺（DA）神经系统的内在差异。在酒精中毒的临床相关性方面，同伴饲养的恒河猴具有显著的面部效度：脑脊液（CSF）中5-HT代谢物5-羟基吲哚乙酸（5-HIAA）的水平降低，乙醇的消耗和耐受性增加，行为冲动和攻击性增加。脑脊液5-HIAA降低与冲动性和高乙醇消耗的关联暗示5-HT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，也涉及冲动和乙醇奖励，也未知。拟议的研究将直接检查5-HT和多巴胺能突触前功能的不同方面，以确定哪些改变与CSF 5-HIAA减少相关。具体目的是：1)利用体内微透析，比较母养和同伴养恒河猴前脑5-HT神经支配的突触前活动。基础细胞外浓度的具体评估将在清醒、主持的动物中使用定量无净通量法确定。5-羟色胺转运体的功能将在相同的研究中通过确定5-羟色胺的体内摄取来评估。2)对母养和同伴养恒河猴前脑和脑干的5-HT转运体进行脑成像。我们将采用微pet方法，采用[11C]DASB，一种高度选择性的5-HT转运体配体，能够标记前脑部位。影像学结果指标将与目的1.3中相同动物中测定的5-羟色胺转运功能指标进行比较)比较清醒母养和同伴饲养动物使用微透析对急性乙醇的腹侧纹状体DA和皮质5-羟色胺的反应性。4)比较母养和同伴饲养动物死后全组织5-羟色胺、5-HIAA、5-羟色胺转运体、DA（及其代谢物）、扣带皮层和腹侧纹状体单胺氧化酶活性。这些值将在个体之间与目标1、2和3中的成像和微透析测量进行比较。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