Neurobiology of Impulsivity and Alcoholism

描述（由申请人提供）：本项目的目的是了解与酒精中毒风险相关的5-羟色胺（5-HT）和多巴胺（DA）神经系统的内在差异。要研究的模型，同龄人饲养的恒河猴，具有显着的表面有效性方面的临床相关的酒精中毒：降低脑脊髓液（CSF）水平的5-羟色胺代谢产物，5-羟基吲哚乙酸（5-HIAA），增加消费，并耐受，乙醇，并增加行为冲动和侵略。CSF 5-HIAA降低与冲动和高酒精消耗的关联暗示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，也与冲动和乙醇奖励有关，也是未知的。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减少有关。具体目标是：1）利用体内微透析技术，比较了母猴与同龄人饲养的恒河猴前脑5-HT神经支配的突触前活动。将使用定量无净通量方法在清醒、主持动物中确定基础细胞外浓度的具体评估。将在相同研究中通过测定5-HT的体内摄取来评估5-HT转运蛋白的功能。2)对母亲饲养和同伴饲养的恒河猴前脑和脑干中的5-HT转运蛋白进行脑成像。我们将采用microPET方法与[11 C]DASB，一个高度选择性的5-HT转运配体能够标记前脑网站。将成像结果测量与在目的1.3）中在相同动物中确定的5-HT转运的功能测量进行比较。在清醒的母亲饲养和同伴饲养的动物中使用微透析比较腹侧纹状体DA和皮质5-HT对急性乙醇的反应性。4)比较死后全组织水平5-HT，5-HIAA，5-HT转运体，DA（及其代谢产物），和单胺氧化酶活性扣带皮层和腹侧纹状体的母亲饲养和同伴饲养的动物。这些值将与目标1、2和3的成像和微透析测量值进行比较。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