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：
10303255
负责人：
SADE MONIQUE SPENCER
金额：
$ 23.25万
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/10303255
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 Cues Cyclic AMP Data Dependence Development Diabetes Mellitus Disease Dominant-Negative Mutation Dopamine Receptor Energy Metabolism Enzymes Extinction (Psychology)FDA approved Foundations 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 Pharmacology 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 base cocaine relapse cocaine relapse prevention cocaine self-administration cocaine use cue reactivity design effective therapy experimental study genetic inhibitor in vivo neuroadaptation neurobiological mechanism novel novel therapeutic intervention novel therapeutics overdose death overexpression preclinical efficacy prevent prophylactic protein kinase inhibitor psychostimulant response sensor 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.

项目概要/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，与可卡因相关的急诊室入院人数和吸毒过量人数激增，令人震惊死亡人数。除了严重的不良健康影响外，长期使用可卡因还会导致适应不良即使在长期禁欲后，神经适应也会产生持久的复发脆弱性。因此，仍然迫切需要找到预防可卡因复发的有效治疗方法，可能会使其中一些神经适应正常化。这项研究的主要目的是确定是否 FDA 批准的糖尿病药物二甲双胍可重新用于治疗可卡因复发公布的数据与其蛋白质靶标之一——腺苷单磷酸激活蛋白激酶（AMPK）相关，可卡因反应。中心假设是二甲双胍通过激活 AMPK。目标 1 旨在确定二甲双胍是否能够减少提示诱导的恢复，即啮齿动物与复发相关，以及这是否取决于 AMPK 激活。我们将确定是否颅内给药伏隔核核心（NAcore）内的二甲双胍，这是一个已知调节提示诱发的复发的大脑区域，足以减少经过自我注射可卡因训练的大鼠的提示诱导恢复。更重要的是，我们将确定二甲双胍的全身给药是否能有效减少复职。在恢复测试之前将立即给予颅内二甲双胍，并在全身注射二甲双胍。在禁欲期间长期给予消退训练。 AMPK 的药物或基因抑制剂用于探测二甲双胍对该激酶的依赖性。当磷酸化（活性）AMPK 减少时在可卡因自我施用和消退后，磷酸-AMPK会因急性可卡因或以下情况而增加提示诱导的恢复测试。目标 2 将测试可卡因相关的 AMPK 活性诱导是否是一个限制奖励的补偿性反应。我们假设观察到的激活 pAMPK 的增加与线索诱导恢复相关的 NAcore 与灭绝有关，而不是与药物寻求有关。记忆操作将用于区分提示消失和提示重新激活，并且 pAMPK 将在 NAcore。最后，我们将评估旨在预激活 AMPK 的二甲双胍预处理是否能够抑制可卡因自我给药的获得，揭示了潜在的预防作用。这些结果有潜力指导可卡因使用障碍的新型治疗干预措施的开发扩大我们对可卡因脆弱性的分子机制的理解范围复发。