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: 3846165
• 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/3846165
• 关键词: 6 hydroxydopamine; NMDA receptors; apomorphine; basal ganglia; caudate nucleus; cell type; corpus striatum; dizocilpine; dopamine; dopamine receptor; electrophysiology; excitatory aminoacid; experimental brain lesion; glutamates; ketamine; lenticular nucleus; neural transmission; neurons; neuropharmacology; neurophysiology; receptor sensitivity; reserpine; stimulant /agonist; substantia nigra

1) Dl and D2 Dopamine Receptors in Basal Ganglia: In Vitro Studies. Studies in striatal slices utilizing intracellular recording techniques find patterns of evoked spike activity and the direction/extent of rectification in current-voltage relationship data are not altered in striatal neurons following 6- week (DA) cell lesion. However, among neurons exhibiting nominal rectification in current-a-voltage relations, a time constant describing the early onset of hyperpolarizing membrane transients was significantly smaller than in control. SKF38393 effects on neuronal excitability are altered after DA cell lesion but this drug's action is unrelated to Dl receptors, raising questions about in vitro use of SKF 38393 as prototypic D1 agonist. 2) In Vivo Effects of Dopamine Agonists: Globus Pallidus. Two distinct globus pallidus cell types have been identified based on their extracellular waveforms and response to DA receptor stimulation. The cells' opposite responses to systemic apomorphine raises questions about basal ganglia circuitry. 3) Consequences of Dopamine Depletion in the Basal Ganglia . Evidence for variability in D1- mediated effects observed: after reserpine treatment, Dl agonist administration leads to an increase in the firing rate of the substantia nigra pars reticulata neurons, an effect exactly opposite to that observed in the 6-OHDA lesioned rats. Moreover, the net result of stimulating both receptor subtypes in the reserpinized preparation was, in fact, opposite to the result obtained when only Dl receptors were stimulated. 4) Role of Excitatory Amino Acid Receptor Subtypes, AMPA, and NMDA in Basal Ganglia Function. The NMDA antagonist dizocilpine had no effect on spontaneous activity in the striatum, globus pallidus, and substantia nigra pars reticulata. Although entopeduncular neurons were partially inhibited by dizocilpine(MK 801). In contrast, the AMPA antagonist NBQX produced a dose-related partial inhibition of activity in the globus pallidus, substantia nigra pars reticulata, and caudate neurons when given systemically. Local infusion of NBQX reduced pallidal activity and partially blocked effects of activating the subthalamic nuclei. Thus, tonic glutamate input serves as a driving force behind some spontaneous activity in various nuclei in the basal ganglia. Studies with glutamate antagonists ketamine and MK801 have indicated that MK801 does not appear to be an effective anesthetic; ketamine anesthesia is neither associated with nor results in a diffuse blockade of the NMDA receptor complex.

1)基底神经节中的D1和D2多巴胺受体：体外研究。 纹状体脑片细胞内记录技术的研究 发现诱发的尖峰活动的模式和方向/程度 电流-电压关系数据中的整流不改变， 纹状体神经元6周（DA）细胞损伤。 然而， 在电流-电压关系中表现出标称整流的神经元， 描述超极化膜早期发生的时间常数 瞬态明显小于对照。 SKF38393效果 对神经元兴奋性的影响在DA细胞损伤后改变， 作用与D1受体无关，引起了关于体外使用的问题。 SKF 38393作为原型D1激动剂。 2)多巴胺激动剂的体内作用：苍白球。 两个不同 苍白球细胞类型已经基于它们的 细胞外波形和对DA受体刺激的反应。 的 细胞对全身性阿扑吗啡的相反反应提出了关于 基底神经节回路 3)基底神经节多巴胺耗竭的后果。证据 观察到的D1介导作用的可变性：利血平处理后， D1激动剂给药导致心肌细胞的放电速率增加， 黑质网状部神经元，与 在6-OHDA损伤大鼠中观察到。 此外，净结果 刺激利血平化制剂中的两种受体亚型， 事实上，与仅D1受体时获得的结果相反， 受刺激 4)兴奋性氨基酸受体亚型、AMPA和NMDA在脑缺血中的作用 基底神经节功能 NMDA拮抗剂地佐环平对 纹状体、苍白球和黑质的自发活动 黑质网状部 虽然脚内核层神经元部分 地佐环平（MK 801）抑制。 相反，AMPA拮抗剂NBQX 在球状体中产生剂量相关的部分抑制活性 苍白球、黑质网状部和尾状核神经元， 系统地给予。 NBQX的局部输注降低了苍白球活性， 部分阻断激活丘脑底核的作用。 因此，在本发明中， 紧张性谷氨酸输入是一些自发性的 在基底神经节中的各种核团中的活性。 谷氨酸研究 氯胺酮拮抗剂和MK801已经表明，MK801不会出现 是一种有效的麻醉剂;氯胺酮麻醉既不与 NOR导致NMDA受体复合物的弥漫性阻断。