The neuropharmacology of brain activation during stages of drug abuse

药物滥用阶段大脑激活的神经药理学

• 批准号: 10681576
• 负责人: Christin Y. Sander
• 金额: $ 50.1万
• 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: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681576
• 关键词: Affect; Award; Brain; Brain imaging; Dopamine; Dopamine Receptor; Drug Addiction; Drug Exposure; Drug abuse; Ensure; Functional Magnetic Resonance Imaging; Future; Glutamates; Image; Knowledge; Measures; Methodology; Molecular; Multimodal Imaging; Neuronal Plasticity; Neuropharmacology; Neurotransmitters; Pharmaceutical Preparations; Positron-Emission Tomography; Rewards; Role; Sensory Receptors; Signal Transduction; Stimulant; System; Therapeutic Intervention; Time; Work; addiction; addiction liability; connectome; drug of abuse; drug reward; experimental study; imaging approach; insight; multimodality; neuroadaptation; neurochemistry; neuroimaging; neurotransmission; new therapeutic target; nonhuman primate; novel; pharmacologic; programs; receptor; response; reward processing; stimulant exposure; tool

Project Summary Dopamine lies at the center of drug reward. All drugs with addiction potential increase dopamine levels in the brain in their initial action, whether directly or indirectly. However, drugs of abuse also engage other neurotransmitters and lead to changes in neuronal signaling affecting distributed functional circuitry. Especially in the long term, the modulation of brain activation in response to repeated drug exposure involves neuroadaptations not only at dopamine receptors but at multiple targets. These non-dopaminergic influences on drug reward processing and addiction have not been extensively investigated but are key to understanding the molecular connectome during stages of drug abuse. For this Avenir Award, we propose to develop pharmacological positron emission tomography (PET) simultaneously with functional magnetic resonance imaging (fMRI) as a platform to study neuroadaptations in multi-receptor systems and their effect on functional signaling and networks in the living brain. Based on previous work developed in our lab for imaging dopamine receptor adaptations, we will develop and validate a multi-modal whole-brain imaging-based approach to disentangle how dopamine interacts with multiple neuroreceptors and neurotransmitter systems. Experiments will be carried out in nonhuman primates to ensure the future translational value of the methodologies and findings. The dynamics of multi-receptor targets will be imaged simultaneously with fMRI at key timepoints during repeated exposure to psychostimulants to develop neuroimaging signatures of receptor adaptations. Pharmacological blocking studies will be paired with stimulant- induced dopamine release to unravel the differential contributions of specific pharmacological targets and related neurotransmitter systems at various time points. Given its pivotal role in neuroplasticity, a focus will be on the involvement of the glutamatergic system and its interplay with dopamine. The insight gained from these classes of experiments will advance novel tools and methodology, and enable us to decipher the neuropharmacology of brain activation during stages of drug exposure. This program has the potential to lead to the revelation of novel drug targets for therapeutic intervention and expand our knowledge about the dynamics of neurochemistry underlying the whole-brain functional circuitry involved in drug addiction.

项目摘要 多巴胺位于药物奖励的中心。所有具有成瘾潜力的药物都会提高多巴胺水平 无论直接还是间接地，大脑在最初的作用中进行大脑。但是，滥用药物也吸引了其他 神经递质并导致影响分布式功能电路的神经元信号传导的变化。尤其 从长远来看，响应重复药物暴露的大脑激活调节涉及 神经适应不仅在多巴胺受体上，而且在多个靶标处。这些非多巴胺能影响 药物奖励处理和成瘾尚未得到广泛的研究，但是理解的关键 药物滥用阶段的分子连接组。 对于这个Avenir奖，我们建议开发药理学正电子发射断层扫描（PET） 同时将功能性磁共振成像（fMRI）作为研究神经适应的平台 多受体系统及其对活大脑中功能信号传导和网络的影响。基于以前的 在我们的实验室成像多巴胺受体适应中开发的工作，我们将开发和验证多模式 基于全脑成像的方法，用于解散多巴胺如何与多个神经受体相互作用， 神经递质系统。实验将在非人类灵长类动物中进行，以确保未来 方法和发现的翻译价值。将成像多受体目标的动力学 在重复接触心理刺激物中，与fMRI同时在关键时刻点发育 受体适应的神经影像学特征。药理阻断研究将与刺激性 - 诱导多巴胺释放以揭示特定药理靶标的差异贡献 神经递质系统在不同时间点。鉴于其在神经可塑性中的关键作用，重点将放在 谷氨酸能系统的参与及其与多巴胺的相互作用。从这些课程中获得的见解 实验将推进新颖的工具和方法论，使我们能够破译 药物暴露阶段的大脑激活。该计划有可能导致新颖的启示 治疗干预的药物目标，并扩大我们对神经化学动态的知识 涉及药物成瘾的整个脑功能电路的基础。