The neuropharmacology of brain activation during stages of drug abuse

项目摘要 多巴胺是药物奖赏的中心。所有具有成瘾潜力的药物都会增加人体内的多巴胺水平 大脑在他们最初的行动中，无论是直接或间接的。然而，滥用毒品也会影响到其他人 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。特别是 从长期来看，对反复接触药物的大脑激活的调节包括 神经适应不仅在多巴胺受体上，而且在多个目标上。这些非多巴胺能影响 毒品奖赏加工和成瘾还没有被广泛调查，但这是理解 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) 同时结合功能磁共振成像(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。基于以前的 我们实验室为成像多巴胺受体适应而开发的工作，我们将开发和验证一种多模式 基于全脑成像的方法解开多巴胺与多个神经受体和 神经递质系统。实验将在非人类灵长类动物身上进行，以确保未来 方法和调查结果的翻译价值。多受体靶点的动态将被成像 在反复接触精神刺激剂期间的关键时间点同时进行功能磁共振成像 受体适应的神经成像特征。药物阻断研究将与兴奋剂配对- 诱导性多巴胺释放解开特定药理靶点的差异贡献及相关 不同时间点的神经递质系统。鉴于它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洞察力 实验将推进新的工具和方法，并使我们能够破译神经药理学 在药物暴露阶段的大脑激活。这个节目有可能导致小说的揭示 治疗干预的药物靶点和扩展我们对神经化学动力学的知识 在参与药物成瘾的全脑功能回路之下。

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.