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。丘脑下丘脑神经元活动增加是多巴胺耗竭状态的一个关键特征，手术干预后这些神经元的失活对缓解帕金森病患者的运动障碍是有效的。因此，重要的是要了解L)这些神经元在正常条件下活性的调节因素，2)黑质多巴胺细胞丢失引起的这些机制的修改如何产生活性增加，以及3)这些变化是否被既定的和实验性的帕金森氏病治疗方法逆转。通过这种方式，应该有可能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下层神经元对谷氨酸、GABA能和多巴胺能受体激活的反应发生长期变化。丘脑下部神经元本身利用谷氨酸作为一种递质。这些神经元的两个主要靶点是黑质网状带和外部苍白球。我们将使用这些结构中的谷氨酸释放，通过微透析法在清醒动物中测量，作为控制和多巴胺耗竭状态下丘脑神经元活性的功能测量，以及在接受以下三种治疗之一的多巴胺耗竭动物中的功能测量：L)慢性L-多巴注射2)丘脑底核的脑深部刺激3)产生γ-氨基丁酸的细胞慢性植入丘脑底核。将比较不同动物组黑质和苍白球谷氨酸释放对丘脑底核谷氨酸、GABA和多巴胺受体激活的反应。行为分析将与这些神经化学测量一起进行，重点是口面部运动障碍的测量。因此，这些体内研究将直接与L项目的分子研究和项目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.