DRUG MECHANISM IN NEURONAL DOPAMINE ORGANIZATI0N

中枢多巴胺(DA)神经元 开发轴突并与其建立功能连接 纹状体(CS)和额叶皮质(FCX)的靶细胞， 而这种连接在细胞存活中的作用是重要的 这些细胞的发育神经生物学中的问题。这 实验室利用一项研究发现了这些发育问题。 体外，分离的细胞-重组系统，其中单个细胞 从小鼠胚胎特定区域制备的悬浮液 大脑被允许自行重组或与细胞重组 来自其他特定的大脑区域。仅当与细胞共培养时 从目标区域，如CS或FCX，DA神经元是否详细说明 广泛的轴突和增强的存活率。这 靶细胞依赖效应对DA神经元发育的影响 与靶细胞膜结合因子(S)。一个 识别和表征这些疾病的免疫学策略 本文介绍了一种利用局部细胞系合成的神经营养因子(S)。 使用这种衍生的细胞系有重要的优点 从这些靶细胞中作为抗原来源来产生 针对该因子的特异性抗体(S)。同质 永生细胞系提供了几乎无限的起点 物质，它们很可能在这些因素中得到丰富 与构成原代的异质细胞群体相比 CS和FCX细胞。来自原代细胞融合的其他细胞系 含有DA的神经元与神经母细胞瘤细胞系一起产生 产生多巴胺浓度相当于 在成年纹状体中发现的那些。进一步刻画 这些含有DA的杂交细胞系与 神经递质合成和神经递质受体是 将此类细胞移植到失神经大鼠体内的前奏 CS试图扭转与此相关的行为异常 帕金森氏病动物模型的多巴胺能神经支配 疾病。最后，脑内DA神经元的功能组织。 与CS的GABA能靶细胞的关系将用以下方法评估 药理工具。靶细胞D-1和D-2的个体发育 受体被允许单独或在存在的情况下发育 将对发育中的多巴胺能神经支配进行检查。这些DA 神经系统是药理作用的重要部位 这些实验应该会产生更多关于 它们的正常发育是细胞和化学物质的函数 发生这种发展的环境。

The manner in which central dopamine (DA)-containing neurons develop axons and establish functional connections with their target cells in the corpus striatum (CS) and frontal cortex (FCx), and the role of such connections in cell survival, are important issues in the developmental neurobiology of these cells. This laboratory has examined these developmental problems using an in vitro, dissociated cell-reaggregation system in which single cell suspensions prepared from specific areas of the embryonic mouse brain are allowed to reaggregate either by themselves or with cells from other specific brain regions. Only when cocultured with cells from target areas such as the CS or FCx do the DA neurons elaborate extensive axonal processes and exhibit enhanced survival. This target cell-dependent effect on DA neuron development is associated with membrane-bound factor(s) of the target cells. An immunological strategy for identifying and characterizing these neuronotrophic factor(s) utilizing local cell lines is described. There are important advantages to using such cell lines derived from these target cells as a source of antigens for generating the specific antibodies directed against the factor(s). Homogeneous immortal cell lines provide practically unlimited starting material, and they are likely to be enriched in these factors compared to the heterogeneous cell population constituting primary CS and FCx cells. Other cell lines derived from fusions of primary DA-containing neurons with a neuroblastoma cell line have produced hybrid cell lines that produce DA in concentrations equivalent to those found in the adult striatum. A further characterization of these DA-containing hybrid cell lines with respect to neurotransmitter synthesis and neurotransmitter receptors is a prelude to the transplantation of such cells into denervated rat CS in an attempt to reverse the behavioral abnormalities associated with dopaminergic denervation, an animal model of Parkison's disease. Finally, the functional organization of DA neurons in relation to GABAergic target cells of the CS will be assessed with pharmacological tools. The ontogeny of target cell D-1 and D-2 receptors allowed to develop, alone, or in the presence of a developing dopaminergic innervation will be examined. These DA neuronal systems are important sites of action for pharmacologic agents, and these experiments should yield further information on their normal development as a function of the cellular and chemical environment in which such development occurs.