FUNCTION OF DOPAMINE IN THE PRIMATE SUBSTANTIA NIGRA

灵长类动物黑质中多巴胺的功能

• 批准号: 8172371
• 负责人: Thomas N Wichmann
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172371
• 关键词: Adverse effects; Affect; Agonist; Anatomy; Animals; Axon; Basal Ganglia; Cell Nucleus; Cells; Computer Retrieval of Information on Scientific Projects Database; Dendrites; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Funding; Glutamates; Grant; Injection of therapeutic agent; Institution; Mediating; Motor; Neurons; Output; Parkinsonian Disorders; Pharmaceutical Preparations; Primates; Process; Psychotic Disorders; Quinpirole; Research; Research Personnel; Resources; Site; Source; Structure of subthalamic nucleus; Substantia nigra structure; Sulpiride; Techniques; United States National Institutes of Health; clinically significant; gamma-Aminobutyric Acid; immunoreactivity; postsynaptic; presynaptic; receptor; response; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We study dopaminergic transmission in the substantia nigra pars reticulata (SNr) of normal and parkinsonian animals, with anatomic and electrophysiologic techniques. We carried out further studies of the anatomic distribution of D2-receptors in SNr, and have expanded the studies to include the other major extrastriatal basal ganglia nuclei, the internal and external pallidal segments (GPi, GPe). The results show that D2-receptor immunoreactivity is found predominately on unmyelinated axons and dendrites in both nuclei. D2-immunoreactive glial processes were also found. We also continued our studies of activation or inactivation of D2-like receptors in these nuclei. We locally injected D2-like receptor agonists and antagonists in two normal animals and two MPTP-treated (parkinsonian) animals, and recorded the neuronal activity in the vicinity of the injection site. Most GPe cells increased their activity in response to quinpirole injections, while the firing rate of GPi and SNr cells decreased. The predominant increase of the discharge rates of GPe neurons may result from activation of presynaptic D2 receptors on striato-pallidal terminals, reducing the release of GABA in GPe. Postsynaptic D4 receptors may also be involved, acting to reduce GABAergic inhibition. The inhibitory effects on GPi/SNr could be mediated through presynaptic inhibition of glutamate release from terminals of inputs from the subthalamic nucleus. Sulpiride injections into GPe, GPi or SNr in normal animals had no effect. The findings are clinically significant, because most of the clinically used dopamine receptor agonists act at D2-like receptors. Our results suggest that these compounds may strongly affect basal ganglia output at extrastriatal sites. The beneficial motor effects of these drugs may mostly result from actions within the motor circuit of the basal ganglia (and may, therefore, predominately involve GPi), while actions at the level of the SNr may explain some of the unwanted side effects of these medications, such as psychosis.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们研究了具有解剖学和电生理技术的正常动物和帕金森氏症动物的底层nigra pars reticulata（SNR）的多巴胺能传播。 我们对SNR中D2受体的解剖分布进行了进一步的研究，并扩大了研究，以包括其他主要的层状室外基底神经节核，内部和外部苍白球段（GPI，GPE）。结果表明，D2受体免疫反应性主要在两个核中的无髓轴突和树突上发现。 还发现了D2免疫反应性神经胶质过程。 我们还继续研究这些核中D2样受体的激活或失活的研究。 我们在两只普通动物和两只经MPTP治疗的（帕金森氏症）动物中局部注射了类似D2的受体激动剂和拮抗剂，并记录了注射部位附近的神经元活性。大多数GPE细胞会响应于奎因螺质注射而增加其活性，而GPI和SNR细胞的发射速率降低。 GPE神经元排放率的主要增加可能是由于纹状体 - 帕利德末端的突触前D2受体的激活导致的，从而减少了GPE中GABA的释放。 突触后D4受体也可能涉及，以减少GABA能抑制作用。 对GPI/SNR的抑制作用可以通过突触前抑制谷氨酸从丘脑下核的输入的末端释放来介导。正常动物中的GPE，GPI或SNR注射硫酸盐无效。 这些发现具有临床意义，因为大多数临床使用的多巴胺受体激动剂作用于D2样受体。 我们的结果表明，这些化合物可能会强烈影响层外部位的基底神经节输出。 这些药物的有益运动作用可能主要是由于基底神经节的运动回路内的作用（因此可能主要涉及GPI），而SNR水平的作用可能解释了这些药物的某些不必要的副作用，例如精神病。