Imaging dopamine receptor adaptations and signaling pathways with combined PET/fMRI

项目摘要/摘要 药物成瘾是一种复杂的神经行为障碍，涉及药物、心理和遗传因素。 影响力。多巴胺受体系统在奖赏和刺激机制中起着重要作用。 上瘾。在突触水平上，敏化是通过动态机制来调节的，如受体 内化；在全脑水平上，适应是通过大脑信号的动态变化来反映的。 这些动态变化，以及药物暴露或治疗如何改变它们，仍然没有被很好地理解 体内，但这是朝着改善药物滥用和相关疾病的治疗选择和结果迈出的关键一步 精神障碍。这项资助的目标是在活体内应用多模式成像，以便研究 滥用的特定药理干预和刺激性药物如何调节受体适应 多巴胺受体系统的机制，并测试防止这种适应的新方法 机械装置。 具有功能磁共振的集成正电子发射断层扫描(PET) 成像(FMRI)将被用来利用已知的诱导受体运输的药物来成像受体运输动力学 D2/D3多巴胺受体的内在化，然后测量这些对兴奋剂的适应性 滥用药物。非人灵长类动物将被成像以建立受体之间的动态关系 占用(PET)和功能激活(FMRI)。与生物物理建模一起，量化 受体转运率及其对功能信号的影响将被量化。最后，参与其中 谷氨酸受体系统的一种防止受体转运的方法将被测试 滥用药物。这种方法将有助于解开针对多巴胺系统的药物的作用及其 在神经生物学进化中的作用发展、维持和最终预防和 毒瘾的治疗。

Project Summary/Abstract Drug addiction is a complex neuro-behavioral disorder, involving pharmacological, psychological and genetic influence. The dopamine receptor system plays a highly relevant role for mechanisms underlying reward and addiction. At the synaptic level, sensitization is mediated through dynamic mechanisms, such as receptor internalization; at the whole-brain level, adaptation is reflected through dynamic changes in brain signaling. These dynamic changes, and how drug exposure or treatment can alter them, are still not well understood in vivo but are a critical step towards improving treatment options and outcomes for substance abuse and related psychiatric disorders. The goal of this grant is to apply in vivo with multi-modal imaging in order to investigate how specific pharmacological interventions and stimulant drugs of abuse modulate receptor adaptation mechanisms of the dopamine receptor system, and test novel approaches to prevent such adaptation mechanisms. State-of-the-art integrated positron emission tomography (PET) with functional magnetic resonance imaging (fMRI) will be used to image receptor trafficking dynamics using drugs that are known to induce receptor internalization at D2/D3 dopamine receptors, and then measure these adaptations for stimulants drugs of abuse. Non-human primates will be imaged to establish dynamic relationships between receptor occupancy (PET) and functional activation (fMRI). Together with biophysical modeling, quantification of receptor trafficking rates and their influence on functional signaling will be quantified. Finally, the involvement of the glutamate receptor system will be tested as an approach to prevent receptor trafficking as induced by drugs of abuse. This approach will help unravel the action of drugs targeted at the dopamine systems and their role in the neurobiological evolution of the development, maintenance and eventual prevention and treatment of drug addiction.