Presynaptic Mechanisms of D1 Receptor Effects on Cortical Function

D1 受体对皮质功能影响的突触前机制

• 批准号: 6893024
• 负责人: CHARLES W BRADBERRY
• 金额: $ 18.98万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-12 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893024
• 关键词: Macaca mulatta; antipsychotic agents; behavior test; behavioral /social science research tag; calcium flux; cognition; cognition disorders; dopamine; dopamine agonists; dopamine antagonists; dopamine receptor; gamma aminobutyrate; glutamates; memory; mental process; neuropharmacology; neuroregulation; neurotransmitter transport; neurotransmitters; prefrontal lobe /cortex; serotonin; visual stimulus

The overall goal of this project is to provide a bridge between the animal studies proposed in the Center on D 1 receptor modification of cortical function with the clinical studies proposed in project 9. Our working hypothesis is that D1 receptor modulation causes state-dependent secondary alterations in the function of other key neurotransmitters such as glutamate, GABA, DA, and serotonin in the prefrontal cortex. Hence, we propose to examine the effect of focal or systemic D1 receptor manipulation, administered in a parallel manner to both the electrophysiological and clinical studies proposed in other projects of this Center, on the release of cortical DA, serotonin, GABA, and glutamate while the animal is under various states that include (1) rest, (2) cognitive activation caused by engagement in working memory task, and (3) cognitive impairment caused by chronic neuroleptic treatment. The specific aims are: 1) Determine the effect of intracortical application of a D1 agonist and antagonist on extracellular efflux of glutamate, GABA, DA, and serotonin in awake, chaired animals at rest or engaged in a working memory task, or a control visually guided task. Based on in vitro and in-vivo analysis of D1 actions, we hypothesize that the D1 agonists will reduce glutamate, GABA, DA and serotonin release. 2) Determine the effect of acute and subchronic systemic treatment with DAS-431 (the D1 agonist to be employed clinically in project 7) on extracellular efflux of glutamate, GABA, DA, and serotonin in chaired animals at rest, engaged in a working memory task, or a control visually guided task. 3) Determine the acute and subchronic effect of DAS-431 on extracellular efflux of glutamate, GABA, DA, and serotonin in animals that have received chronic neuroleptic treatment. Studies will be performed at rest, engaged in a working memory task, or a control visually guided task.

该项目的总体目标是在皮质功能 D 1 受体修饰中心提出的动物研究与项目 9 中提出的临床研究之间架起一座桥梁。我们的工作假设是 D1 受体调节导致状态依赖性继发性改变其他关键神经递质的功能，如前额皮质中的谷氨酸、GABA、DA 和血清素。因此，我们建议检查局灶性或全身性 D1 受体操作的影响，以与本中心其他项目中提出的电生理学和临床研究并行的方式进行。 当动物处于各种状态时，皮质 DA、血清素、GABA 和谷氨酸的释放，包括 (1) 休息，(2) 参与工作记忆任务引起的认知激活，以及 (3) 长期抗精神病药治疗引起的认知障碍。具体目标是： 1) 确定皮质内应用 D1 激动剂和拮抗剂对清醒、坐在椅子上休息或从事工作记忆任务或控制视觉引导任务的动物的谷氨酸、GABA、DA 和血清素细胞外流出的影响。基于 D1 作用的体外和体内分析，我们假设 D1 激动剂会减少谷氨酸、GABA、DA 和血清素的释放。 2) 确定 DAS-431（项目 7 中临床使用的 D1 激动剂）急性和亚慢性全身治疗对处于工作记忆状态的休息动物中谷氨酸、GABA、DA 和血清素细胞外流出的影响任务，或控制视觉引导任务。 3) 确定 DAS-431 对接受慢性抗精神病药物治疗的动物中谷氨酸、GABA、DA 和血清素细胞外流出的急性和亚慢性影响。研究将在休息时进行，参与工作记忆任务或控制视觉引导任务。