REGIONAL VARIATION IN D1 SIGNALING PROTEIN LOCALIZATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 前额叶皮质(PFC)、伏隔核(NAC)和杏仁核形成一个皮质边缘环路，参与正常认知、精神分裂症、焦虑和恐惧状态、奖励通路和药物滥用。作用于D1受体家族的多巴胺对这些大脑区域的个体和集体功能至关重要。在报告期间，我们对这些受体的细胞行为的研究发现，它们在一个区域内的影响以及这些大脑区域之间的差异。我们的工作继续研究这种可变性的结构基础。以往的研究表明，D1家族受体在信号转导偶联过程中存在区域差异。在过去的一年里，我们的研究检查了这些蛋白在PFC、NAC和杏仁核的亚细胞定位。 我们的研究主要集中在D1族多巴胺受体亚型D1和D5，以及信号转导蛋白DARPP-32、抑制物-1和蛋白磷酸酶-1。我们的研究结果阐明了关于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影响的理解。这一信息有助于合理开发与皮质边缘回路相关的疾病的药物治疗，包括精神分裂症、药物滥用和焦虑症，包括创伤后应激障碍。 这些疾病困扰着我们的大量退伍军人，目前的治疗选择效果有限。为了与退伍军人管理局的病人护理使命保持一致，将对与这些疾病相关的基本神经生物学过程进行进一步研究。

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.