Chronic alterations in functional response to glutamate, GABA and dopamine

丘底核在控制基底冈神经输出中起着关键作用。丘脑下神经元活动的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肌动症。因此，了解1)在正常情况下调节这些神经元活动的因素，2)黑质中多巴胺细胞的缺失如何引起这些机制的改变，以及3)这些变化是否可以通过帕金森病的既定和实验性治疗来逆转是很重要的。通过这种方式，应该有可能开发出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导致丘脑下神经元对谷氨酸能、gaba能和多巴胺能受体激活的反应发生长期变化。丘脑下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目标是黑质网状带和外苍白球。我们将利用这些结构中的谷氨酸释放，在有意识的动物中通过微透析来测量，作为控制和多巴胺缺失状态下丘脑下神经元活动的功能测量，以及在接受三种治疗之一的多巴胺缺失动物中：1)慢性左旋多巴管理2)丘脑下核深部脑刺激3)慢性植入丘脑下核中产生gaba的细胞。在这些不同的动物群体中，我们将比较黑质和苍白球谷氨酸释放对丘脑下核谷氨酸、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同时进行，重点是对口面部运动障碍的测量。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.