Novel Addiction Neurocircuits in Cocaine Taking

项目摘要 可卡因使用障碍（CUD）在美国是一个令人衰弱的问题，没有FDA批准的药物， 最大限度地提高治疗效果。2019冠状病毒病大流行加剧了这一问题， 去年，可卡因的使用增加了10%，过量死亡增加了26.5%。 涉及可卡因我们奋进推动新的战略，为CUD开发新的药物疗法。使用 自下而上的策略，我们开始关注腹侧苍白球（VP），它编码奖励和动机， 代表可卡因吸食的“最终共同途径”。我们对上游神经系统的理解 调节VP的回路阻碍了我们预测抑制复发和延长 从CUD的禁欲。我们令人兴奋的新数据表明，γ-氨基丁酸（GABA）途径出现在 中缝背核和靶向延髓核会聚到VP中以影响奖赏， 激励过程。这一新的通路受G蛋白偶联受体神经介肽U受体的调节 2（NMUR 2），一个公认的CUD药物治疗的“可用药靶标”。我们的目标是建立这种神经回路 作为可卡因驱动行为的上游控制中的中心元素，通过VP的Escherebal途径。 为了实现这一目标，我们将采用当代的战略，包括行为经济学，特定的GABA DREADDs和跨突触神经解剖追踪通过三个集成的大脑详细连接 地区总的来说，这些研究将通过为开发治疗方法奠定基础来影响该领域。 个人CUD

PROJECT SUMMARY Cocaine use disorder (CUD) is a debilitating problem in the United States with no FDA approved medications to maximize success of treatment. This problem has been exacerbated by the COVID-19 pandemic, and over the past year, cocaine use has increased 10% and a 26.5% increase has been observed in overdose deaths involving cocaine. We endeavor to drive a fresh strategy to develop new pharmacotherapies for CUD. Using a bottom-up strategy, we initiated a focus on the ventral pallidum (VP) which encodes reward and motivation to represent a “final common pathway” for cocaine-taking. A gap in our understanding of the upstream neural circuits regulating the VP hampers our efficacy in predicting strategies to suppress relapse and extend abstinence from CUD. Our exciting new data suggest that a γ-aminobutyric acid (GABA) pathway arising in the dorsal raphe nucleus and targeting the nucleus accumbens converges into the VP to influence reward and motivation processes. This novel pathway is regulated by the G-protein coupled receptor neuromedin U Receptor 2 (NMUR2), a putative “druggable target” for CUD pharmacotherapy. Our goal is to establish this neurocircuitry as a central element in the upstream control of cocaine-driven behavior through the VP of the accumbal pathway. To accomplish this goal, we will employ contemporary strategies including behavioral economics, GABA-specific DREADDs and transsynaptic neuroanatomical tracing to detail connectivity through three integrated brain regions. Overall, these studies will impact the field by laying the foundation for developing therapeutics to treat individuals with CUD.