Novel Addiction Neurocircuits in Cocaine Taking

项目总结 可卡因使用障碍(CUD)在美国是一个令人衰弱的问题，没有FDA批准的药物来 最大限度地提高治疗成功率。这个问题因新冠肺炎大流行而加剧，而且在 去年，可卡因的使用增加了10%，过量死亡人数增加了26.5% 涉及可卡因。我们努力推动一种新的战略，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 代表了吸食可卡因的“最终共同途径”。我们对上游神经的理解上的差距 调节VP的回路阻碍了我们预测抑制复发和扩大复发的策略的有效性 戒除禁欲。我们令人兴奋的新数据表明，γ-氨基丁酸(GABA)途径出现在 中缝背核和靶向伏隔核汇聚成VP影响奖赏和 激励过程。这一新途径受G蛋白偶联受体Neuromedin U受体的调节 2(NMUR2)，可能是CUD药物治疗的“可用药靶点”。我们的目标是建立这个神经回路 作为通过伏隔通路的VP上游控制可卡因驱动的行为的中心元素。 为了实现这一目标，我们将采用当代策略，包括行为经济学、GABA特定策略。 DREADDS和跨突触神经解剖学追踪通过三个整合的大脑细节连接 地区。总体而言，这些研究将通过为开发治疗方法奠定基础来影响该领域 患有CUD的个体。

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.