The neuropharmacology of brain activation during stages of drug abuse

项目摘要 多巴胺是药物奖赏的核心。所有具有成瘾潜力的药物都会增加大脑中的多巴胺水平。 大脑在其最初的行动，无论是直接或间接。然而，滥用药物也涉及其他 神经递质并导致影响分布式功能电路的神经元信号的变化。尤其 从长远来看，对反复药物暴露的大脑激活的调节包括： 神经适应不仅在多巴胺受体，但在多个目标。这些非多巴胺能影响 药物奖励过程和成瘾尚未得到广泛的研究，但这是理解药物成瘾的关键。 药物滥用阶段的分子连接体 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） 与此同时，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脑中功能信号和网络的影响。基于先前 在我们实验室开发的多巴胺受体适应成像工作中，我们将开发和验证多模式 基于全脑成像的方法来解开多巴胺如何与多种神经受体相互作用， 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 方法和结果的转化价值。多受体靶点的动态将被成像 在重复暴露于精神兴奋剂期间的关键时间点同时进行fMRI， 受体适应性的神经影像特征。药理学阻断研究将与兴奋剂- 诱导多巴胺释放，以解开特定药理学靶点和相关 不同时间点的神经递质系统。鉴于其在神经可塑性中的关键作用，重点将放在 多巴胺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 实验将推进新的工具和方法，使我们能够破译神经药理学的 在药物暴露阶段的大脑激活。这一计划有可能导致小说的启示 药物靶点的治疗干预和扩大我们的知识动态的神经化学 这是与药物成瘾有关的全脑功能回路的基础。

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.