Novel Addiction Neurocircuits in Cocaine Taking

可卡因吸食中的新型成瘾神经回路

• 批准号: 10375964
• 负责人: Kathryn A. Cunningham
• 金额: $ 48.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375964
• 关键词: Abstinence; Affect; Affinity; Anatomy; Behavior; Biological; Biological Assay; Biology; Brain; Brain region; COVID-19 pandemic; Chronic; Cocaine; Cocaine use disorder; Consumption; Data; Elements; FDA approved; Foundations; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Globus Pallidus; Goals; Health; Human; Hyperactivity; Incentives; Individual; Intake; Ligands; Link; Maps; Mass Spectrum Analysis; Mediating; Medical; Microdialysis; Modeling; Motivation; Neural Pathways; Neuromedin U; Neurons; Neuropeptides; Neurotransmitters; Nucleus Accumbens; Outcome; Output; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Protocols documentation; Publishing; Rattus; Relapse; Research; Resources; Rewards; Rodent Model; Role; Self Administration; Signal Transduction; Structure; Substance Use Disorder; Synapses; System; Technology; Testing; Texas; Therapeutic; United States; Universities; Viral Vector; addiction; base; behavioral economics; cocaine exposure; cocaine self-administration; cocaine use; designer receptors exclusively activated by designer drugs; dorsal raphe nucleus; druggable target; gamma-Aminobutyric Acid; innovation; knock-down; motivational processes; neural circuit; neuromedin U receptor; neurotransmitter release; novel; novel therapeutics; overdose death; pre-clinical research; presynaptic; psychosocial; relating to nervous system; sex; success; theories

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.

项目概要 可卡因使用障碍 (CUD) 在美国是一个令人衰弱的问题，目前还没有 FDA 批准的药物可以治疗 最大限度地提高治疗成功率。 COVID-19 大流行加剧了这个问题，并且在过去 去年，可卡因使用量增加了 10%，过量死亡人数增加了 26.5% 涉及可卡因。我们致力于推动新的战略来开发针对 CUD 的新药物疗法。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 代表了可卡因吸食的“最终共同途径”。我们对上游神经元的理解存在差距 调节 VP 的回路阻碍了我们预测抑制复发和延长治疗策略的效率 戒除 CUD。我们令人兴奋的新数据表明，γ-氨基丁酸（GABA）途径出现在 中缝背核和伏隔核汇聚到 VP 中以影响奖赏和 动机过程。该新途径受 G 蛋白偶联受体神经调节素 U 受体调节 2 (NMUR2)，CUD 药物治疗的假定“可成药靶点”。我们的目标是建立这种神经回路 作为通过accumbal途径的VP上游控制可卡因驱动行为的核心元件。 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 DREADD 和跨突触神经解剖学追踪通过三个集成大脑详细连接 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 患有 CUD 的个人。