Stimulant-induced excitatory and inhibitory dopamine receptor signaling and trafficking

兴奋剂诱导的兴奋性和抑制性多巴胺受体信号传导和运输

• 批准号: 10734322
• 负责人: Christin Y. Sander
• 金额: $ 69.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734322
• 关键词: Acute; Address; Affect; Amphetamines; Animal Model; Behavior; Brain; Chronic; Complex; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dopamine Uptake Inhibitors; Drug Addiction; Drug Exposure; Drug Kinetics; Drug Sensitization; Drug abuse; Drug usage; Drug user; Equilibrium; Evolution; Experimental Designs; Exposure to; Functional Magnetic Resonance Imaging; Goals; Hour; Image; In Vitro; Injections; Knowledge; Lead; Maintenance; Measures; Membrane; Methodology; Methods; Molecular; Multimodal Imaging; Neurobiology; Neuropharmacology; Outcome; Pathogenesis; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Prevention; Raclopride; Receptor Signaling; Recovery; Recycling; Reporting; Ritalin; Role; Sensory Receptors; Signal Transduction; Stimulant; Substance Use Disorder; Synapses; Testing; Time; addiction; antagonist; dopamine system; dopamine transporter; extracellular; imaging study; in vivo; innovation; insight; neurobiological mechanism; neuroimaging; nonhuman primate; pharmacologic; prevent; psychostimulant; radiotracer; receptor; receptor internalization; receptor recycling; response; stimulant abuse; stimulant exposure; stimulant use; timeline; trafficking; translation to humans; uptake

Project Summary The dopamine system plays a major role in the pathogenesis of substance use disorders. Stimulant drug use and abuse lead to several dopaminergic alterations that contribute to the complex behavior associated with the formation of addiction. A single acute exposure to a stimulant drug can trigger receptor internalization as an early synaptic adaptation mechanism to high dopamine concentrations. These mechanisms have been shown to affect neuroimaging outcomes, specifically positron emission tomography (PET), which has revealed paradoxically long reductions in dopamine D2/D3 receptor availability after stimulant-induced dopamine release. To date, we still have a limited understanding of the timeline of dopamine receptor internalization and recovery with repeated drug exposure and how these adaptation mechanisms affect whole-brain signaling of both excitatory D1 and inhibitory D2-type receptors. This study aims to address this knowledge gap by characterizing how two classes of stimulant drugs (amphetamine and methylphenidate) modulate dopamine receptor subtype signaling and receptor trafficking over time. Using state-of-the-art simultaneous PET and functional magnetic resonance imaging (fMRI) methodology in non-human primates, the timescales of amphetamine-induced receptor internalization and recycling will be established using repeated amphetamine administrations. Targeted dopaminergic blocking drugs will be paired with amphetamine to determine how the balance between excitatory D1 and inhibitory D2 receptor signaling and trafficking is modulated over time. The effects of repeated amphetamine will then be compared to those of methylphenidate to assess varying levels of dopamine surges and differential mechanisms of action across these two stimulant drugs. Overall, this study will unravel brain- wide molecular and functional changes due to repeated stimulant drug exposure by imaging the timescales of dopamine receptor trafficking in the living brain in a translational animal model. The results will elucidate the role of dopamine D1 and D2-type receptor adaptations, thereby providing important insight into the neurobiological mechanisms involved in repeated stimulant drug use relevant for initiating and eventually preventing drug sensitization and addiction.

项目摘要 多巴胺系统在物质使用障碍的发病机制中起主要作用。兴奋药物使用 和滥用导致几种多巴胺能的改变，这些改变导致与 形成成瘾。单次急性暴露于刺激性药物可以触发受体内化， 突触适应机制，以高多巴胺浓度。这些机制已被证明会影响 神经影像学结果，特别是正电子发射断层扫描（PET），这表明矛盾的是， 在兴奋剂诱导的多巴胺释放后，多巴胺D2/D3受体的可用性长期下降。迄今为止，我们 我仍然对多巴胺受体内化和恢复的时间轴有有限的理解， 药物暴露以及这些适应机制如何影响兴奋性D1和 抑制性D2型受体。本研究旨在通过描述两个类如何解决这一知识差距 兴奋剂（安非他明和哌甲酯）调节多巴胺受体亚型信号传导， 随着时间的推移受体的运输。使用最先进的同步PET和功能磁共振 在非人灵长类动物中，安非他明诱导的受体的时间尺度 将通过反复给予安非他明来建立内化和再循环。针对性 多巴胺能阻断药物将与安非他明配对，以确定兴奋性之间的平衡如何， D1和抑制性D2受体信号传导和运输随时间调节。重复的影响 然后将安非他明与哌醋甲酯进行比较，以评估多巴胺激增的不同水平 以及这两种兴奋剂的不同作用机制。总的来说，这项研究将解开大脑- 广泛的分子和功能的变化，由于重复刺激药物暴露，通过成像的时间尺度， 多巴胺受体在转译动物模型中的活脑中的运输。结果将阐明 多巴胺D1和D2型受体适应，从而提供了重要的洞察神经生物学 涉及重复使用兴奋剂的机制与启动和最终预防药物 致敏和成瘾。