Chronic alterations in functional response to glutamate, GABA and dopamine

对谷氨酸、GABA 和多巴胺的功能反应的慢性改变

• 批准号: 6254648
• 负责人: Nigel T Maidment
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6254648
• 关键词: GABA receptor; Parkinson's disease; abnormal involuntary movement; basal ganglia; behavioral /social science research tag; brain electrical activity; dihydroxyphenylalanine; dopamine receptor; glutamate receptor; glutamates; laboratory rat; lenticular nucleus; microdialysis; neurochemistry; neurotransmitter transport; receptor expression; substantia nigra; subthalamus

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.

丘脑下核在控制基底帮派的输出中起关键作用。 胸甲酸下神经元的活性增加是多巴胺耗尽状态的关键特征，手术干预后这些神经元的失活可有效减轻帕金森氏病患者的甲基氨基疾病。 因此，重要的是要了解l）在正常条件下调节这些神经元活性的因素，2）如何通过在质体中丧失多巴胺细胞引起的这些机制的修饰会产生其活性的增加，而3）如果这些变化被帕克森病的既定且实验性治疗逆转。 这样，应该有可能开发针对这些神经元的新药理方法。我们假设多巴胺耗竭会引起胸甲神经元对谷氨酸能，GABA能和多巴那素能受体激活的长期变化。 丘脑下神经元本身利用谷氨酸作为发射机。 这些神经元的两个主要靶标是黑质Nigra Zona reticulata和外部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丘脑下核。在这些不同的动物组中，比较了丘脑下核中谷氨酸，GABA和多巴胺受体激活对谷氨酸，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有关，重点是口面性运动障碍。 因此，这些体内研究将与项目L的分子研究以及项目2的体外电生理方法直接接触。