Repurposing Metformin as a Treatment for Cocaine Use Disorder

项目摘要 可卡因使用障碍（CUD）是一种慢性复发性疾病，导致能量稳态的神经适应 在反复的药物暴露之后。目前没有FDA批准的治疗方法可以降低复发的风险。 CUD。据报道，美国每年因可卡因死亡的人数从2013年的4，939人增加了近五倍 到2021年将增加到24，538人，使其成为一个重大的公共卫生问题。尽管最近的科学进步阐明了 关键的神经回路和生物条件，驱动可卡因寻求行为，发展 事实证明，采取干预措施打破成瘾的重复循环较为困难。操作行为模型 药物自我管理，消退，和线索诱导的恢复模拟线索启动和药物渴求， 恢复期患者经历与过去药物使用相关的环境、线索或记忆。渴望和复发 可卡因寻求是由NAcC中的谷氨酸能（Glu）神经传递驱动的，在两个人类中观察到， 动物模型。临床上，可卡因复吸的易感性在女性患者中明显较高， 对可卡因的强烈渴望这种显著的性别差异，也反映在动物模型中， CUD代表了治疗开发中的一个障碍，该障碍在不同性别之间产生治疗益处。我们的实验室 二甲双胍（MET）是FDA批准的II型糖尿病（T2D）治疗药物， 减少提示诱导的可卡因复吸的承诺，当给药时， 在雌性和雄性大鼠的颅内。我自己的初步数据显示，全身二甲双胍可以减少 可卡因在雄性大鼠中的条件性奖励效应。在T2D中，MET部分改善了血糖管理 通过激活腺苷一磷酸活化蛋白激酶（AMPK），当其磷酸化时， 恢复细胞内AMP与ATP的比率以响应环境应激。AMPK降低， 慢性暴露于可卡因后，MET诱导AMPK增加 活性，从而提供了一个有希望的推定的作用机制。尽管如此，口服MET的效果如何仍然未知。 生物分布到NAcC，以及它如何影响可卡因复吸事件背后的关键Glu回路。这 研究将通过定义中心药效学和药代动力学来探索MET的治疗潜力 在NAcC中口服MET。该提案测试了以下假设：口服MET将：1）具有更高的 雄性大鼠自我给药后，对减少线索诱导的可卡因寻求行为有明显作用， 与雌性大鼠相比，2）通过激活AMPK减少线索诱导的恢复，3）增加Glu NAcC中的神经传递降低了线索相关谷氨酸传递的信噪比， 通过体内纤维光度法测量。拟议工作的目标是提供重要证据， 支持MET作为CUD治疗的潜在再利用。

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.