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: 6478896
• 负责人: Nigel T Maidment
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6478896
• 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.

丘脑底核在控制基底神经节的输出中起着关键作用。 丘脑下神经元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 l) 在正常条件下调节这些神经元活动的因素，2) 黑质中多巴胺细胞损失引起的这些机制的改变如何导致其活动增加，以及 3) 如果这些变化帕金森病的已建立和实验性治疗方法可逆转这些症状。 通过这种方式，应该有可能开发出针对这些神经元的新药理学治疗方法。我们假设多巴胺耗竭会导致丘脑下神经元对谷氨酸能、GABA 能和多巴能受体激活的反应发生长期变化。 丘脑底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，通过微透析在有意识的动物中测量，作为控制和多巴胺耗尽状态下丘脑底神经元活动的功能测量，以及在接受以下三种治疗之一的多巴胺耗尽动物中：l)慢性L -多巴给药2)丘脑底核的深部脑刺激3)在丘脑底核中长期植入产生GABA的细胞。将在这些不同组的动物中比较黑质和苍白球谷氨酸释放对底丘脑核中谷氨酸、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，重点关注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 的体外电生理学方法相结合。