NEUROCHEMISTRY OF STRIATUM--ALTERATION BY DA DEPLETING LESIONS

本计画将著重于儿茶酚胺的适应特性 神经元，因为它们与神经元损伤有关。 我们的主要 一种假说认为多巴胺（DA）既发挥突触作用， 对背侧纹状体中靶细胞的非突触影响， 在DA耗竭损伤后，非突触通讯和 大运动行为是幸免，直到DA损失是广泛的，而 突触沟通和更微妙的运动能力， 与受伤程度大致成比例地被破坏。 拟议 我们将继续研究动物模型， 其中部分损伤的DA-含有投射的 黑质纹状体通路在大鼠中由脑内 注射6-羟基多巴胺（6-OHDA）。 四套 实验提出：首先，我们将确定的程度， 多巴胺能的影响在部分丧失后仍然存在 DA输入到背侧纹状体作为损伤大小的函数， 术后时间和左旋多巴的可用性。 DA对其靶点影响的神经生物学测量 完整和病变动物将包括：乙酰胆碱（Ach） 释放（D2介导的反应），cAMP产生（主要是 和D1-反应），和GABA释放（一个复杂的相互作用 包括D1和D2位点）。 第二，我们将开展 使用行为终点的平行研究，包括食物和 水摄入量，运动活动，操作反应时间，和 神经系统成套测试 在第三个实验系列中，我们将 探讨终端损耗和 功能缺陷，重点是DA损伤引起的变化 DA自身受体的敏感性和多巴胺能神经递质的变化 输入. 最后，我们将研究与酪氨酸有关的变化 多巴胺部分损伤后羟化酶基因表达 神经元，比较我们的结果从那些获得的反应， 去甲肾上腺素能神经元损伤。 数额变动 将检查供应到神经末梢的TH， 终端内TH稳定性的变化。 率 TH合成也将被测量，重点是TH基因的速率 转录和翻译。 我们认为， 将对我们的研究产生影响 了解帕金森症的原因和治疗，并将 还提供了关于神经生物学的重要信息， 多巴胺能神经元及其与脑内神经元的相互作用 基底神经节

This project will focus on the adaptive properties of catecholamine neurons as they relate to neuronal injury. Our principal hypothesis is that dopamine (DA) exerts both a synaptic and a non-synaptic influence on target cells in the dorsal striatum and that after DA-depleting lesions non-synaptic communication and gross motor behavior is spared until DA loss is extensive, whereas synaptic communication and more subtle motoric capabilities are disrupted in rough proportion to the injury. In the proposed experiments we will continue our examination of an animal model in which partial injury of the DA-containing projections of the nigrostriatal pathway is produced in rats by the intracerebral injection of 6-hydroxydopamine (6-OHDA). Four sets of experiments are proposed: First, we will determine the extent to which a dopaminergic influence is preserved after the partial loss of the DA input to dorsal striatum as a function of lesion size, post-operative time, and the availability of L-DOPA. Neurobiological measures of the impact of DA on its targets in intact and lesioned animals will include: acetylcholine (Ach) release (a D2-mediated response), cAMP production (primarily and D1-response), and GABA release (a complex interaction involving both D1 and D2 sites). Second, we will carry out parallel studies using behavioral endpoints, including food and water intake, motor activity, operant reaction time, and a neurological test battery. In the third experimental series we will explore the basis for the discrepancies between terminal loss and functional deficits, focussing on lesion-induced changes in DA synthesis, DA autoreceptor sensitivity, and changes glutamatergic input. Finally, we will examine the changes related to tyrosine hydroxylase (TH) gene expression after partial injury of DA neurons, comparing our results from those obtained in response to damage to noradrenergic neurons. Alterations in the amount of TH supplied to the nerve terminal will be examined, as will changes in the stability of TH within the terminal. The rate of TH synthesis also will be measured, focusing on rate of TH gene transcription and translation. We believe that the findings that will emerge from this research will have implications for understanding the cause and treatment of Parkinsonism, and will also provide important information regarding the neurobiology of dopaminergic neurons and their interactions with neurons in the basal ganglia.