Chronic alterations in functional response to glutamate, GABA and dopamine

丘脑底核在控制基底神经节的输出中起着关键作用！IA。 丘脑底核神经元的活性增加是多巴胺耗尽状态的一个关键特征，手术干预后这些神经元的失活可有效缓解帕金森病患者的运动不能。 因此，重要的是要了解1）在正常条件下调节这些神经元活动的因素，2）黑质多巴胺细胞损失引起的这些机制的修改如何增加其活动，以及3）这些变化是否被帕金森病的既定和实验性治疗逆转。 通过这种方式，应该可以开发针对这些神经元的新的药理学治疗方法。我们假设多巴胺耗竭诱导丘脑底核神经元对多巴胺能、GABA能和多巴胺能受体激活的反应发生长期变化。 底丘脑神经元本身利用谷氨酸作为递质。 这些神经元的两个主要目标是黑质网状核和外部苍白球。 我们将使用在这些结构中的谷氨酸释放，通过在清醒动物中的微透析测量，作为在对照和多巴胺耗尽状态下以及在经历以下三种治疗之一的多巴胺耗尽动物中的丘脑底神经元的活性的功能测量：1）慢性L-DOPA施用2）丘脑底核的深部脑刺激3）在丘脑底核中的GABA产生细胞的慢性植入。将在这些不同组动物中比较黑质和苍白球对丘脑底核中谷氨酸、GABA和多巴胺受体激活的谷氨酸释放反应。 行为分析将与这些神经化学测量同时进行，重点是口面运动障碍的测量。 因此，这些体内研究将直接与项目1的分子研究和项目2的体外电生理方法相结合。

The subthalamic nucleus plays a critical role in controlling the output of the basal gang!ia. An increased activity of subthalarnic neurons is a key feature of the dopamine-depleted state, and inactivation of these neurons following surgical intervention is effective in alleviating akinesia in Parkinson's disease patients. It is therefore important to understand l) the factors regulating the activity of these neurons under normal conditions, 2) how modification of these mechanisms induced by loss of dopamine cells in the substantia nigra produces an increase in their activity, and 3) if these changes are reversed by established and experimental treatments for Parkinson's disease. In this way it should be possible to develop new pharmacological approaches to therapy which target these neurons. We hypothesize that dopamine depletion induces long-term changes in the response of subthalarnic neurons to glutamatergic, GABAergic and dopaninergic receptor activation. Subthalamic neurons themselves utilize glutamate as a transmitter. Two major targets of these neurons are the substantia nigra zona reticulata and the external pallidum. We will use glutamate release in these structures, measured by microdialysis in conscious animals, as a functional measure of the activity of subthalamic neurons in control and dopamine-depleted states, and in dopamine-depleted animals undergoing one of three treatments: l) chronic L-DOPA administration 2) deep brain stimulation of the subthalamic nucleus 3) chronic implantation of GABA-producing cells in the subthalamic nucleus. The substantia nigra and globus pallidus glutamate release response to activation of glutamate, GABA and dopamine receptors in the subthalamic nucleus will be compared in these different groups of animals. Behavioral analyses will be carried out concomitant with these neurochemical measurements, focusing on measures of orofacial dyskinesia. These in vivo studies will therefore directly interface with the molecular studies of Project l and with the in vitro electrophysiological approach of project 2.