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Targeting adenosine monophosphate activated protein kinase (AMPK) to reduce cocaine relapse

靶向单磷酸腺苷激活蛋白激酶 (AMPK) 减少可卡因复吸

基本信息

批准号：
10593045
负责人：
SADE MONIQUE SPENCER
金额：
$ 19.38万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593045
关键词：
Abstinence Accident and Emergency department Acute Adenosine Monophosphate Admission activity Adverse effects Allosteric Regulation Amphetamines Animal Model Antidiabetic Drugs Brain Brain region Ca(2+)-Calmodulin Dependent Protein Kinase Chronic Clinical Cocaine Cocaine use disorder Cue-induced relapse Cues Cyclic AMP Data Dependence Development Diabetes Mellitus Disease Dominant-Negative Mutation Dopamine Receptor Energy Metabolism Enzymes Extinction FDA approved Future Gelatinases Goals Health Impairment Infusion procedures Inhibition of Matrix Metalloproteinases Pathway Link Measures Mediating Memory Metformin Methamphetamine Microinjections Molecular Neurobiology Nucleus Accumbens Oxidative Stress Penetrance Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphotransferases Protein Kinase Proteins Publishing Rattus Receptor Activation Relapse Research Rewards Rodent Role STK11 gene Signal Transduction Substance Use Disorder Synaptic plasticity Testing Training Validation Western Blotting addiction cocaine relapse cocaine relapse prevention cocaine reward cocaine seeking cocaine self-administration cocaine use constitutive expression design effective therapy experimental study genetic inhibitor in vivo neuroadaptation neurobiological mechanism novel novel therapeutic intervention novel therapeutics overdose death overexpression pharmacologic preclinical efficacy prevent prophylactic protein kinase inhibitor psychostimulant response sensor therapy design transmission process upstream kinase

项目摘要

Project Summary/Abstract Despite years of research there are still no approved pharmacotherapies for treatment of cocaine use disorder. Recently, there has been an alarming surge in cocaine-associated emergency room admissions and overdose deaths. In addition to acute adverse health effects, protracted use of cocaine results in maladaptive neuroadaptations that produce an enduring vulnerability to relapse even after extended abstinence. Consequently there remains a critical need to identify effective treatments for cocaine relapse prevention that may normalize some of these neuroadaptations. The primary objective of this research is to determine if the FDA-approved diabetes drug metformin can be repurposed for the treatment of cocaine relapse based on published data linking one of its protein targets, adenosine monophosphate activated protein kinase (AMPK), to cocaine responses. The central hypothesis is that metformin reduces cocaine seeking through activation of AMPK. Aim 1 is designed to determine if metformin is able to reduce cue-induced reinstatement, the rodent correlate of relapse, and if this depends on AMPK activation. We will determine if intracranial administration of metformin within the nucleus accumbens core (NAcore), a brain region known to regulate cue-induced relapse, is sufficient to reduce cue-induced reinstatement in rats trained to self-administer cocaine. More importantly, we will establish whether systemic administration of metformin is effective at reducing reinstatement. Intracranial metformin will be delivered acutely prior to a reinstatement test, and systemic metformin will be given chronically during abstinence with extinction training. Pharmacologic or genetic inhibitors of AMPK will be used to probe metformin's dependence on this kinase. While phosphorylated (active) AMPK is reduced following cocaine self-administration and extinction, phospho-AMPK is increased by acute cocaine or following a cue-induced reinstatement test. Aim 2 will test whether the cocaine-related induction of AMPK activity is a compensatory response to limit reward. We hypothesize that the observed increase in the activated pAMPK in NAcore associated with cue-induced reinstatement is related to extinction rather than drug seeking. Memory manipulations will be used to distinguish cue extinction from cue reactivation and pAMPK will be measured in NAcore. Lastly, we will assess whether metformin pretreatment designed to pre-activate AMPK is capable of inhibiting the acquisition of cocaine self-administration revealing potential prophylactic effects. These results have the potential to guide development of novel therapeutic interventions for cocaine use disorder and broaden the scope of our understanding of the molecular mechanisms underlying vulnerability to cocaine relapse.

项目总结/摘要尽管经过多年的研究，仍然没有批准用于治疗可卡因使用障碍的药物疗法。最近，与可卡因有关的急诊室入院和过量服用的情况出现了惊人的激增死亡除了严重的不良健康影响外，长期使用可卡因还导致适应不良神经适应性，即使在长期禁欲后，也会产生持久的复发脆弱性。因此，仍然迫切需要确定预防可卡因复吸的有效治疗方法，可以使这些神经适应正常化。本研究的主要目的是确定 FDA批准的糖尿病药物二甲双胍可以重新用于治疗可卡因复发，已发表的数据将其蛋白质靶点之一，腺苷一磷酸活化蛋白激酶（AMPK），可卡因的反应。中心假设是二甲双胍通过激活 AMPK。目的1旨在确定二甲双胍是否能够减少啮齿动物线索诱导的复发，与复发相关，如果这取决于AMPK激活。我们将确定颅内注射二甲双胍在脑桥核核心（NAcore），一个已知调节线索诱导复发的大脑区域，足以减少训练自我施用可卡因的大鼠的线索诱导的恢复。更重要的是，我们将确定全身给予二甲双胍是否能有效减少复发。在恢复试验之前，将立即给予颅内二甲双胍，在禁欲期间长期服用并进行灭绝训练。AMPK的药理学或遗传学抑制剂将是用于探测二甲双胍对这种激酶的依赖性。当磷酸化（活性）AMPK减少时，在可卡因自我给药和消退后，磷酸化AMPK通过急性可卡因或线索诱导复原测试目的2将测试可卡因相关的AMPK活性诱导是否是一个重要的因素。限制奖励的补偿反应。我们推测，在细胞中观察到的激活的pAMPK的增加，与线索诱导的恢复相关的NAcore与灭绝有关，而不是药物寻求。存储器操作将用于区分线索消退与线索再激活， NAcore。最后，我们将评估二甲双胍预处理是否能够预先激活AMPK，抑制可卡因自我给药的获得，揭示了潜在的预防作用。这些结果有可能指导开发可卡因使用障碍的新型治疗干预措施，扩大我们对可卡因脆弱性的分子机制的理解范围复发