PROJECT 2 - D1 receptor endocytosis and signaling

这是一个非常成功的项目的续订申请，该项目之前曾详细阐述过突触后 阿片和多巴胺受体的调节。重建计划中建议进行的研究亦会研究 突触前隔区，特别集中在DL型多巴胺受体，调节直接 纹状体/伏隔核GABA能输出通路及其调控的精确评价 突触囊泡从轴突中吐出。拟议研究的具体目标是： 具体目标1.确定快速DIR贩运事件是否仅限于躯体树突表面 或者也出现在MSN的轴突中。 明确细胞外DA动力学和电活动对DL-R内吞作用的影响 MSNS。 具体目标3.确定DIR转运对突触前和突触后信号的功能影响。 拟议的实验将确定直接通路的多巴胺能调节的基本特性， 它控制着自然的动机行为，对五种成瘾药物的强化作用至关重要。这个 研究还直接测试并从机制上阐明了DL受体对突触前的调节作用。这是一个 细胞神经科学的基本领域，即可能揭示操纵成瘾的新方法 吸毒或治疗成瘾五大障碍。 相关性(请参阅说明)： 纹状体中棘神经元中的多巴胺信号控制着对天然Sfimuli和 调节成瘾药物的强化作用。拟议的研究确定了这种信号是如何工作的， 并检验了关于它如何被自然刺激重新调整到药物中的具体假设。今年5月 识别成瘾性毒品的特点，以进行治疗靶点。

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 funcfional consequences of DIR trafficking on pre- and post- synapfic signaling. The proposed experiments will define the basic properties of dopaminergic regulafion ofthe direct pathway, which controls natural motivated behavior and is critical for the reinforcing effects of addicfive drugs. The studies also directly test, and mechanistically elucidate, presynaptic regulafion by Dl receptors. This is a fundamental area of cellular neuroscience that is may reveal new approaches for manipulating addictove drug acfion or treating addicfive disorders. RELEVANCE (See instructions): Dopamine signaling in medium spiny neurons ofthe striatum control montivafion to natural sfimuli and mediate the reinforcing effects of addictive drugs. The proposed studies determin how this signaling works, and examines specific hypotheses for how it is regualted by natural stimuli relafive to drugs. This may idenfify specific features of addictive drug acfion for therapeutic targefing.