PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

这个项目的目标是阐明特定的功能， 调节基底神经元信息处理的神经元系统 神经节，以确定可以操纵的机制， 预防、纠正和/或补偿涉及这些的功能障碍 系统. 在1995财政年度，重点放在以下影响的过程上： 多巴胺受体亚型对基底神经节输出的影响。 (1)丘脑底核：在体细胞外单个单位记录 出乎意料地表明，无论是在局部还是系统上， 施用的多巴胺D1激动剂对脑皮层产生兴奋作用， 丘脑底核神经元的活动。全身效应被局部阻断 输注D1拮抗剂。 D2/D3激动剂诱导较小的变化， 底丘脑活动，尽管D2/D3受体的紧张性内源性张力 似乎需要D1介导的作用。放射自显影技术 已经证明了丘脑底核中的D2/D3受体和D1 感受器位于大脑脚附近的腹侧边缘; 推测位于兴奋性皮层传入神经的末梢。因此，在本发明中， 除了作用于纹状体苍白球和纹状体黑质神经元之外， 多巴胺能药物也可对神经元产生功能上的显著影响。 基底神经节通过对皮层输入的作用输出 丘脑底核在帕金森病的动物模型中， 丘脑底核的活动增强， 多巴胺激动剂发生显着改变。非选择性多巴胺激动剂 诱导损伤大鼠丘脑底活动减少， 与正常动物相比， 机制正在 调查，并可能与苍白球切开术的疗效在 帕金森病的治疗 (2)纹状体：大鼠纹状体核内AP-1转录因子的结合 结合后蛋白提取物以协同方式增强， 全身给予D1和D2/D3激动剂。这些结果 证明D1和D2/D3受体介导的协同相互作用 诱导纹状体基因表达以及神经元活性变化 但不能指出受体亚型的定位。注入 选择性D1和D2激动剂局部进入6-OHDA损伤的纹状体 大鼠纹状体中的Fos蛋白产生变化;然而， 与基底神经节输出的改变不一致， SNpr中的发射率。 结果表明，D1和D2受体在 纹状体以及纹状体外部位的D1受体是必需的 用于介导与D1相关的基底神经节输出的变化， D2-D3多巴胺受体刺激。

The goal of this project is to elucidate the function of specific neuronal systems in regulating information processing in the basal ganglia in order to identify mechanisms which could be manipulated to prevent, correct and/or compensate for dysfunction involving these systems. In FY95, focus has been on processes underlying the effects of dopamine receptor subtypes on basal ganglia output. (1) Subthalamic nucleus: In vivo extracellular single unit recordings have shown, unexpectedly, that locally as well as systemically administered dopamine D1 agonists exert excitatory effects on the activity of subthalamic neurons. Systemic effects are blocked by local infusion with a D1 antagonist. D2/D3 agonists induce less change in subthalamic activity although tonic endogenous tone at D2/D3 receptors appears required for the D1-mediated effects. Autoradiographic techniques have demonstrated D2/D3 receptors in the subthalamic nucleus and D1 receptors on the ventral border adjacent to the cerebral peduncle; presumably located on terminals of excitatory cortical afferents. Thus, in addition to acting on striatopallidal and striatonigral neurons, dopaminergic agents also may exert functionally significant effects on basal ganglia output through actions on cortical inputs to the subthalamic nucleus. In animal models of Parkinson's disease, tonic activity in the subthalamic nucleus is enhanced and the responses to dopamine agonists is markedly altered. Nonselective dopamine agonist induces decreases in subthalamic activity in the lesioned rats as compared to increases in normal animals. Mechanisms are being investigated and may be relevant to the efficacy of pallidotomies in the treatment of Parkinson's disease. (2) Striatum: AP-1 transcription factor binding in rat striatal nuclear protein extract is enhanced in a synergistic manner after combined systemic administration of D1 and D2/D3 agonists. These results demonstrate that D1 and D2/D3 receptor-mediated synergistic interactions induce changes in striatal gene expression as well as neuronal activity but do not indicate where the receptor subtypes are localized. Infusing selective D1 and D2 agonists locally into the striatum in 6-OHDA-lesioned rats produces changes in Fos protein in the striatum; however, this does not coincide with alterations in basal ganglia output as measured by firing rates in the SNpr. Results indicate that D1 and D2 receptors in the striatum as well as D1 receptors at extrastriatal sites are necessary for mediating the changes in basal ganglia output associated with D1 and D2-D3 dopamine receptor stimulation.