Repurposing Metformin as a Treatment for Cocaine Use Disorder

重新利用二甲双胍治疗可卡因使用障碍

• 批准号: 10823844
• 负责人: Edith Hernandez
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-27 至 2027-09-26
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10823844
• 关键词: Abstinence; Adenosine Monophosphate; Adult; Animal Model; Annual Reports; Antisense Oligonucleotides; Behavior; Behavioral; Behavioral Model; Biodistribution; Biological; Biosensor; Brain; Central Nervous System; Central Nervous System Agents; Cessation of life; Chronic; Clinical; Cocaine; Cocaine use disorder; Collaborations; Cues; Data; Development; Dose; Down-Regulation; Drug Exposure; Drug Modelings; Drug usage; Event; Extinction; FDA approved; Female; Fiber; Glucose; Glutamates; Goals; Homeostasis; Intervention; Measures; Medical; Memory; Metformin; Methods; Microinjections; Minnesota; Modeling; Molecular; Mus; Neurons; Neuropharmacology; Noise; Non-Insulin-Dependent Diabetes Mellitus; Nucleus Accumbens; Operative Surgical Procedures; Oral; Oral Administration; Oral Ingestion; Outcome; Patients; Pharmaceutical Preparations; Phosphorylation; Photometry; Physicians; Positioning Attribute; Predisposition; Protein Kinase; Psychiatry; Public Health; Rattus; Recovery; Recurrent disease; Relapse; Reporting; Research; Rewards; Risk Reduction; Safety; Scientific Advances and Accomplishments; Scientist; Self Administration; Sex Differences; Signal Transduction; Site; Stimulant; Surveys; Testing; Therapeutic; Therapeutic Effect; Time; Training; Translating; United States; Universities; Withdrawal; Work; addiction; blood-brain barrier crossing; brain tissue; cocaine cue; cocaine exposure; cocaine overdose; cocaine relapse; cocaine seeking; cocaine self-administration; cost; craving; drug craving; environmental stressor; experience; experimental study; human model; human subject; improved; in vivo; knock-down; liquid chromatography mass spectrometry; male; neuroadaptation; neuronal circuitry; neurotransmission; novel; overdose risk; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; relapse risk; response; sex; therapy development; translational model; transmission process

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.

项目摘要 可卡因使用障碍（CUD）是一种慢性复发疾病，导致能量稳态的神经适应 反复暴露药物后。目前尚无FDA批准的治疗可降低复发的风险 库德。据报道，涉及可卡因的年死亡在2013年的4,939人几乎在美国的Quintuplepl 到2021年为24,538，这使得这是一个主要的公共卫生问题。尽管最近阐明了科学进步 关键的神经元电路和驱动可卡因寻求可卡因行为的生物条件，发展 事实证明，破坏成瘾重复周期的干预措施更加困难。操作行为模型 药物自我给药，灭绝和提示诱导的恢复原状模仿提示启动和渴望 康复中的患者经历了与过去药物使用相关的环境，提示或记忆。渴望和复发 在NACC中，寻求可卡因的寻求是由谷氨酸能（GLU）神经传递驱动的 和动物模型。临床上，报告可卡因复发的易感性明显更高 更渴望可卡因生成的提示。这种重大的性别差异也反映在动物模型中 CUD代表了治疗开发的障碍，可以在性别中产生治疗益处。我们的实验室有 证明了二甲双胍（Met）是FDA批准的II型糖尿病（T2D）治疗 在给药后撤离后恢复提示引起的可卡因恢复原状的承诺 颅内和雄性大鼠颅内。我自己的初步数据表明，全身二甲双胍可减少 可卡因对雄性大鼠的有条件奖励作用。在T2D中，MET改善了葡萄糖管理部分 通过激活腺苷单磷酸激活的蛋白激酶（AMPK），当磷酸化时， 响应环境应激源，恢复AMP与ATP的细胞内比率。 AMPK在 长期暴露于可卡因后，伏隔核（NACC）随着MET诱导的AMPK增加 活动因此提供了有希望的推定作用机制。尽管如此，仍然未知口头满足 生物分布与NACC及其如何影响可卡因复发事件的关键GLU电路。这 研究将通过定义中央药效和药代动力学来探索MET的治疗潜力 在NACC中遇到的口腔。该提案检验了Met的口服给药的假设：1） 在减少雄性大鼠自我管理后的提示引起的可卡因寻求行为方面的强大效果 与雌性大鼠相比，2）通过激活AMPK减少提示诱导的恢复，3）增强GLU NACC中的神经传递将信号降低至与提示相关的谷氨酸传播的噪声 通过体内纤维光度法测量。拟议工作的目的是提供重要的证据表明 支持MET的潜在重新利用作为对CUD的治疗。