REGIONAL VARIATION IN D1 SIGNALING PROTEIN LOCALIZATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 前额叶皮层（PFC），杏仁核（NAc）和杏仁核形成了一个皮质边缘回路，参与正常认知，精神分裂症，焦虑和恐惧状态，奖励途径和药物滥用。多巴胺作用于D1受体家族，对这些大脑区域的个体和集体功能至关重要。在本报告所述期间，我们对这些受体的细胞作用进行的研究发现，它们在一个区域内的作用存在差异，在这些大脑区域之间也存在差异。我们的工作继续研究这种变异性的结构基础。以前的工作表明D1家族受体的信号转导偶联的区域差异。在过去的一年中，我们的研究探讨了这些蛋白质在PFC，NAc和杏仁核的亚细胞定位。 我们的研究集中在D1家族多巴胺受体亚型D1和D5，以及信号转导蛋白DARPP-32，抑制剂-1和蛋白磷酸酶-1。我们的研究结果阐明了D1受体作用的相互矛盾的生理学研究，并促进了我们对多巴胺能药物对这些重要脑区的作用的理解。这一信息有助于合理开发药物治疗与皮质边缘回路有关的疾病，包括精神分裂症、药物滥用和焦虑症，包括创伤后应激障碍。 这些疾病困扰着大量的退伍军人，目前的治疗方案效果有限。为了与VA的患者护理使命保持一致，将在与这些疾病相关的基本神经生物学过程中进行进一步的研究。

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. The prefrontal cortex (PFC), nucleus accumbens (NAc) and amygdala form a corticolimbic circuit that is involved in normal cognition, schizophrenia, anxiety and fear states, reward pathways and drug abuse. Dopamine, acting at the D1 family of receptors is critical to the individual and collective function of these brain regions. During the reporting period, our studies of the cellular actions of these receptors found variability in their effects within a region as well as variation between these brain regions. Our work continues to study the structural basis for this variability. Previous work demonstrated regional differences in the signal transduction coupling of D1 family receptors. During the past year, our studies examined the subcellular localization of these proteins in PFC, NAc and amygdala. Our studies focused on the D1 family dopamine receptor subtypes, D1 and D5, as well as the signal transduction proteins DARPP-32, Inhibitor-1 and protein phosphatase-1. The results of our studies have shed light on conflicting physiological studies of D1 receptor action and advance our understanding of the effect dopaminergic drugs have on these important brain regions. This information adds to the rational development of pharmacotherapies for the disorders associated with the corticolimbic circuit, including schizophrenia, substance abuse and anxiety disorders, including PTSD. These disorders afflict a large number of our Veterans and current treatment options are of limited effectiveness. In keeping with the patient care mission of the VA, further research will be done in the basic neurobiological processes related to these disorders.