PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA

黑质和基底神经节的药理学和生理学

• 批准号: 6162990
• 负责人: J R WALTERS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162990
• 关键词: 6 hydroxydopamine; Parkinson's disease; basal ganglia; brain electrical activity; brain mapping; corpus striatum; disease /disorder model; dopamine agonists; dopamine antagonists; dopamine receptor; electrophysiology; experimental brain lesion; laboratory rat; neural information processing; neuropharmacology; neurophysiology; receptor sensitivity; single cell analysis; substantia nigra; transcription factor

Investigations into the role of dopamine (DA) in basal ganglia (BG) function in FY97 have focused on the subthalamic nucleus (STN), an area emerging as critical to the generation of Parkinson's disease (PD) symptomatology, and regions directly innervated by the STN, the substantia nigra pars reticulata (SNpr) and globus pallidus (GP). Extracellular single unit recording studies in intact rats with a series of full D1 receptor agonists have confirmed previous results obtained with a partial D1 agonist (SKF 38393) demonstrating that D1 receptor stimulation markedly enhances STN activity but does not exert consistent effects on SNpr and GP neurons in the absence of agonist-induced increases in D2 receptor stimulation. STN firing rates are also increased by systemically administered D1/D2 agonists but require a specific order of receptor stimulation; D2 agonists do not alter STN firing rates. These effects are inconsistent with current models of basal ganglia function and argue for important dopaminergic effects on basal ganglia output mediated via interactions with glutamatergic corticosubthalamic projections and/or direct effects on STN neurons. In a rodent model of PD [unilateral 6-hydroxydopamine(6-OHDA)-induced lesion of the median forebrain bundle], effects of DA D1/D2 agonists on STN activity are qualitatively altered. Consistent with the observation that STN lesion reduces the symptomatology of PD in man, extracellular single unit recordings in rats show STN neuronal firing rates are doubled after DA cell lesion, and reduced by systemic administration of L-DOPA or DA D1/D2 receptor agonists. These findings together with the observation that unilateral STN lesion markedly attenuates DA agonist- induced rotation in this rodent model of PD argues that STN neurons are critically involved in the hypo- and hyperactivity associated with altered levels of DA receptor stimulation in PD. Ongoing studies are focused on identifying how changes in STN activity mediate these effects. Results to date show the firing pattern of STN neurons in 6- OHDA lesioned rats becomes less burst-like; glutamatergic NMDA antagonists further reduce burst activity and attenuate D1 agonist- induced increases in STN firing rates. In the SNpr, studies of neuronal firing rate and pattern in 6-OHDA-lesioned rats have produced the unexpected finding that DA agonist induced rotational behavior does not correlate with decreases in SNpr neuronal firing rates. Dramatic changes in firing pattern have been observed, however, which involve DA agonist-induced oscillations in instantaneous frequency in the range of 0.25 - 0.05 Hz in SNpr as well as other BG nuclei. New techniques for quantifying this previously undescribed attribute of BG neuronal activity have been developed in FY97 and are being used to quantitate the effects of altering DA receptor stimulation on these oscillations within the basal ganglia nuclei.

多巴胺在基底节的作用研究 1997财年的功能主要集中在丘脑底核(STN)，这是一个区域 成为帕金森氏病(PD)发生的关键因素 症状学，以及STN直接支配的区域， 黑质网状部(SNPR)和苍白球(GP)。 一系列完整大鼠细胞外单单位记录的研究 的全部d1受体激动剂证实了先前的结果 用部分D1激动剂(SKF 38393)证明D1受体 刺激显著增强STN活性，但作用不一致 不使用激动剂对SNPR和GP神经元的影响 D2受体刺激增加。STN的开机率也是 由系统给药的D1/D2激动剂增加，但需要 受体刺激的特定顺序；D2激动剂不改变STN 射击率。这些影响与当前的模型不一致 基底节功能与多巴胺能在脑内的重要作用 与谷氨酸能相互作用介导的基底节输出 皮质-下丘脑投射和/或对STN神经元的直接影响。 单侧6-羟基多巴胺(6-OHDA)诱导的大鼠帕金森病模型 前脑正中束损伤]，多巴胺D_1/D_2激动剂对 STN活性发生质的改变。与观察到的一致 STN损毁可减轻人类帕金森病的症状，细胞外 大鼠的单单位记录显示，STN神经元的放电频率是 DA细胞损伤后增加一倍，全身给药减少 L-多巴或多巴胺D1/D2受体激动剂。这些发现与 损毁单侧STN可明显减弱DA激动剂-- 这种帕金森病啮齿动物模型的诱导旋转认为，STN神经元是 严重地参与了与以下相关的低度和过度活动 帕金森病患者DA受体刺激水平改变。正在进行的研究包括 重点是确定STN活动的变化如何调节这些 效果。到目前为止的结果显示，STN神经元在6个月内的放电模式。 OHDA损毁大鼠变得不那么突发性；谷氨酸能NMDA 拮抗剂进一步降低猝发活性并减弱D1激动剂- 诱发STN放电频率的增加。在SNPR中，神经元的研究 6-OHDA损毁大鼠的放电频率和模式产生了 意外发现DA激动剂诱导的旋转行为不 与SNPR神经元放电率的降低有关。戏剧性 然而，已经观察到放电模式的变化，这涉及到DA 激动剂诱导的瞬时频率振荡在以下范围内 SNPR和其他BG核的频率为0.25-0.05赫兹。新技术可用于 量化BG神经元这一以前未描述的属性 活动已在97财年开发，并正在用于量化 改变DA受体刺激对这些振荡的影响 在基底节核团内。