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: 3968918
• 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/3968918
• 关键词: Huntington's disease; Parkinson's disease; basal ganglia; central nervous system; central nervous system disorders; centrally acting drug; cerebrospinal fluid; dopamine; drug metabolism; evoked potentials; extrapyramidal disorder; fluorimetry; gamma aminobutyrate; glutamate decarboxylase; mental disorder chemotherapy; neurochemistry; neuromuscular disorder chemotherapy; neuropharmacology; neurophysiology; neurotoxins; neurotransmitter biosynthesis; neurotransmitter metabolism; neurotransmitters; pilocarpine; probenecid; radioimmunoassay; radiotracer; substantia nigra

1) The D-1 dopamine receptor in basal ganglia function. It has previously been assumed that the dopamine receptor responsible for mediating dopamine effects on behavior is the D-2 dopamine receptor; the function of D-1 receptors has been unclear. However, we have shown that the effects of D-2 agonists on the activity of basal ganglia output neurons are significantly potentiated by coadministration of a selective D-1 receptor agonist. Moreoever, effects of D-2 agonists when given alone appear dependent on endogenous dopamine providing some D-1 receptor stimulation. These studies indicate that D-1 and D-2 receptors interact synergistically to affect striatal output and demonstrate the apparent necessity for both receptors to be simultaneously stimulated for the induction of processes previously thought independently mediated by the D-2 receptor. 2) Selective modulation of dopamine autoreceptor function. If dopamine autoreceptors constitute a distinct subset of D-2 dopamine receptors which can be stimulated selectively by a specific agonist, such a drug might have therapeutic advantages in the treatment of tardive dyskinesia, schizophrenia and parkinsonism. We have defined the properties of two new drugs selected for potentially selectivity for dopamine autoreceptors. Both drugs, BHT920 and EMD38362, were found to be more effective agonists at dopamine autoreceptors than at postsynaptic dopamine receptors but each drug has some distinctive properties. These drugs will allow exploration of the therapeutic potential of selective dopamine autoreceptor stimulation and insight into the properties of the dopamine autoreceptors. 3) Consequences of dopamine receptor denervation. Neurophysiological evidence supports the idea that the consequences of stimulating D-1 dopamine receptors are altered by chronic denervation, and shows significant synergistic interactions between the dopamine receptor subtypes occur in the denervated rat. These studies and the effects of bromocriptine in the denervated rat model and in parkinsonian patients suggest that a nonselective dopamine agonist would have a greater efficacy in parkinsonism than an agonist selective for one dopamine receptor subtype.

1)D-1多巴胺受体在基底神经节功能中的作用 其原先已经 一直认为负责调节多巴胺的多巴胺受体 影响行为的是D-2多巴胺受体; D-1的功能 受体尚不清楚。 然而，我们已经表明，D-2的影响 激动剂对基底神经节输出神经元的活性的影响显著 通过共同施用选择性D-1受体激动剂而增强。 此外，单独给药时，D-2激动剂的作用似乎依赖于 内源性多巴胺提供一些D-1受体刺激。 这些研究 表明D-1和D-2受体协同作用影响 纹状体输出并证明这两种受体的明显必要性 同时被刺激以诱导先前的过程， 被认为是由D-2受体独立介导的。 2)多巴胺自身受体功能的选择性调节。 如果多巴胺 自身受体构成D-2多巴胺受体的独特亚类， 可以通过特定的激动剂选择性地刺激，这种药物可能具有 在治疗迟发性运动障碍中的治疗优势， 精神分裂症和帕金森综合症。 我们定义了两个新的 选择对多巴胺自身受体具有潜在选择性的药物。 发现BHT 920和EMD 38362这两种药物是更有效的激动剂 比突触后多巴胺受体更容易， 药物具有一些独特的特性。 这些药物将允许探索 选择性多巴胺自身受体刺激的治疗潜力 以及对多巴胺自身受体特性的深入了解。 3)多巴胺受体去神经支配的后果。 神经生理 有证据表明，刺激D-1的结果 多巴胺受体被慢性去神经支配改变， 多巴胺受体亚型之间的显著协同作用 发生在失神经大鼠。 这些研究以及 溴隐亭在失神经大鼠模型和帕金森病患者中的作用 表明非选择性多巴胺受体激动剂 在帕金森症中比对一种多巴胺受体亚型有选择性的激动剂更有效。