Repurposing Metformin as a Treatment for Cocaine Use Disorder

项目总结 可卡因使用障碍(Cud)是一种慢性复发性疾病，导致能量平衡的神经适应。 在反复接触毒品之后。目前还没有FDA批准的治疗方法来降低癌症复发的风险 丘德。据报道，美国每年与可卡因有关的死亡人数比2013年的4939人增加了近四倍 到2021年将增加到24,538人，这使其成为一个主要的公共卫生问题。尽管最近的科学进步阐明了 驱动可卡因寻找行为的关键神经回路和生物条件，发展 事实证明，中断成瘾反复循环的干预措施更加困难。操作型行为模型 药物自我给药、灭绝和线索诱导的恢复模拟线索启动和药物渴求 正在康复中的患者正在经历与过去药物使用相关的环境、线索或记忆。渴望和故态复萌 在两人中观察到，寻找可卡因是由NACC中的谷氨酸(Glu)神经传递驱动的 和动物模型。临床上，有报告的女性患者对可卡因复发的易感性明显更高。 对可卡因配对线索的强烈渴望。这种显著的性别差异也反映在 CUD代表了治疗开发中的一个障碍，它产生了跨性别的治疗益处。我们的实验室有 证实了FDA批准的II型糖尿病(T2D)治疗药物二甲双胍(MET)已进入临床前阶段 承诺减少线索诱导的可卡因在停药一段时间后恢复 在雌性和雄性大鼠的脑内。我自己的初步数据显示，全身二甲双胍降低了 可卡因对雄性大鼠的条件奖赏效应。在T2D中，MET在一定程度上改善了血糖管理 通过激活腺苷一磷酸激活的蛋白激酶(AMPK)，当磷酸化时， 恢复细胞内AMP/ATP的比率，以应对环境应激。AMPK在 慢性可卡因暴露后伏隔核核(NACC)，Met诱导的AMPK增加 活动，从而提供了一个有希望的假定的行动机制。尽管如此，口头会面的程度仍然是未知的。 生物分布到NACC以及它可能如何影响导致可卡因复发事件的关键谷氨酸回路。这 研究将通过定义中枢药效学和药代动力学来探索MET的治疗潜力 在全国反兴奋剂机构的口头会面。这项建议验证了口服MET的假设：1)有更多的 给药后对雄性大鼠线索诱导的可卡因寻求行为的影响 与雌性大鼠相比，2)通过激活AMPK减少线索诱导的恢复，3)增强Glu NACC中的神经传递降低线索相关谷氨酸传递的信噪比 用活体纤维光度法测量。拟议工作的目标是提供重要的证据 支持将MET作为治疗CUD的潜在再用途。

PROJECT SUMMARY Cocaine use disorder (CUD) is a chronic relapsing disease that leads to neuroadaptations in energy homeostasis after repeated drug exposure. There is currently no FDA-approved treatment that lowers the risk of relapse in CUD. Reported annual deaths involving cocaine have nearly quintupled in the United States from 4,939 in 2013 to 24,538 in 2021, making this a major public health concern. Despite recent scientific advances elucidating critical neuronal circuitry and biological conditions that drive cocaine-seeking behaviors, the development of interventions to disrupt the repeating cycle of addiction has proved more difficult. The operant behavioral model of drug self-administration, extinction, and cue-induced reinstatement emulates cue priming and drug craving in patients in recovery experiencing settings, cues, or memories associated with past drug use. Craving and relapse of cocaine seeking is driven by glutamatergic (Glu) neurotransmission in the NAcC, observed in both humans and animal models. Clinically, susceptibility to cocaine relapse is notably higher in female patients with reports of stronger craving to cocaine-paired cues. This significant sex difference, also reflected in animal models of CUD, represents an obstacle in treatment development that yields therapeutic benefit across sexes. Our lab has demonstrated that metformin (MET), an FDA-approved Type II Diabetes (T2D) treatment, has pre-clinical promise in reducing cue-induced cocaine reinstatement after a period of withdrawal when administered intracranially in both female and male rats. My own preliminary data shows that systemic metformin reduces the conditioned rewarding effects of cocaine in male rats. In T2D, MET improves glucose management in part through activation of adenosine monophosphate activated protein kinase (AMPK), which when phosphorylated, restores the intracellular ratio of AMP to ATP in response to environmental stressors. AMPK is decreased in the nucleus accumbens core (NAcC) after chronic exposure to cocaine, with MET-induced increases in AMPK activity thus providing a promising putative mechanism of action. Still, it remains unknown how oral MET is biodistributed to the NAcC and how it may impact critical Glu circuitry underlying cocaine relapse events. This study will explore the therapeutic potential of MET by defining central pharmacodynamics and pharmacokinetics of oral MET in the NAcC. This proposal tests the hypotheses that oral administration of MET will: 1) have a more robust effect in reducing cue-induced cocaine-seeking behavior after self-administration in male rats as compared to female rats, 2) reduce cue-induced reinstatement via activation of AMPK, and 3) augment Glu neurotransmission in the NAcC reducing the signal to noise of cue-associated glutamate transmission as measured by in vivo fiber photometry. The goal of the proposed work is to provide significant evidence that supports the potential repurposing of MET as a treatment for CUD.