PROJECT 2 - D1 receptor endocytosis and signaling

项目总结（见说明）： 这是一个非常成功的项目，以前阐述了阿片和多巴胺受体的突触后调节的更新应用。更新中提出的研究还将检查突触前区室，特别关注调节纹状体/中脑核GABA能输出的直接途径的D1型多巴胺受体，并精确评估突触囊泡从轴突胞吐的调节。拟议研究的具体目标是： 具体目标1。确定快速的神经元贩运事件是否仅限于体树突表面或也发生在MSN的轴突。 具体目标2。定义细胞外DA动力学和电活动对MSN中D1 R内吞作用的影响。 具体目标3。识别突触前和突触后信号传导中的神经递质运输的功能后果. 这些实验将确定多巴胺能直接通路调节的基本特性，该通路控制自然动机行为，对成瘾药物的强化作用至关重要。这些研究还直接测试并机械地阐明了D1受体的突触前调节。这是细胞神经科学的一个基本领域，可能揭示操纵成瘾药物作用或治疗成瘾性疾病的新方法。

PROJECT SUMMARY (See instructions): This is a renewal application of a highly successful project that has previously elaborated postsynaptic regulation of opioid and dopamine receptors. The studies proposed in the renewal will examine also the presynaptic compartment, specifically focusing on Dl-type dopamine receptors that regulate the direct pathway GABAergic output from striatum / nucleus accumbens, and to precise evaluation ofthe regulation of synaptic vesicle exocytosis from axons. The Specific Aims of the proposed studies are: Specific Aim 1. Determine whether rapid DIR trafficking events are restricted to the somatodendritic surface or occur also in axons of MSNs. Specific Aim 2. Define the effects of extracellular DA dynamics and electrical activity on Dl R endocytosis in MSNs. Specific Aim 3. Identify functional consequences of DIR trafficking on pre- and post- synaptic signaling. The proposed experiments will define the basic properties of dopaminergic regulation ofthe direct pathway, which controls natural motivated behavior and is critical for the reinforcing effects of addictive drugs. The studies also directly test, and mechanistically elucidate, presynaptic regulation by Dl receptors. This is a fundamental area of cellular neuroscience that is may reveal new approaches for manipulating addictive drug action or treating addictive disorders.