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:
- 金额:$ 23.25万
- 依托单位:
- 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:
- 关键词:AbstinenceAccident and Emergency departmentAcuteAdenosine MonophosphateAdmission activityAdverse effectsAllosteric RegulationAmphetaminesAnimal ModelAntidiabetic DrugsBrainBrain regionCa(2+)-Calmodulin Dependent Protein KinaseChronicClinicalCocaineCocaine use disorderCuesCyclic AMPDataDependenceDevelopmentDiabetes MellitusDiseaseDominant-Negative MutationDopamine ReceptorEnergy MetabolismEnzymesExtinction (Psychology)FDA approvedFoundationsFutureGelatinasesGoalsHealthImpairmentInfusion proceduresInhibition of Matrix Metalloproteinases PathwayLinkMeasuresMediatingMemoryMetforminMethamphetamineMicroinjectionsMolecularNeurobiologyNucleus AccumbensOxidative StressPenetrancePharmaceutical PreparationsPharmacologyPharmacotherapyPhosphorylationPhosphotransferasesProtein KinaseProteinsPublishingRattusReceptor ActivationRelapseResearchRewardsRodentRoleSTK11 geneSignal TransductionSubstance Use DisorderSynaptic plasticityTestingTrainingValidationWestern Blottingaddictionbasecocaine relapsecocaine relapse preventioncocaine self-administrationcocaine usecue reactivitydesigneffective therapyexperimental studygenetic inhibitorin vivoneuroadaptationneurobiological mechanismnovelnovel therapeutic interventionnovel therapeuticsoverdose deathoverexpressionpreclinical efficacypreventprophylacticprotein kinase inhibitorpsychostimulantresponsesensortransmission processupstream 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.
项目摘要/摘要
尽管进行了多年的研究,但仍没有获得批准的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过量服药人数激增,令人震惊
死亡。除了对健康的严重不良影响外,长期使用可卡因还会导致适应不良
神经适应,即使在长期禁欲后,也会产生持久的复发脆弱性。
因此,仍然迫切需要确定有效的预防可卡因复发的治疗方法,
可能会使其中一些神经适应正常化。这项研究的主要目标是确定
FDA批准的糖尿病药物二甲双胍可以改变用途,用于治疗可卡因复发
公布的数据表明,它的蛋白质靶标之一--一磷酸腺苷活化蛋白激酶(AMPK)--
对可卡因的反应。中心假说是,二甲双胍通过激活
AMPK。目的1是为了确定二甲双胍是否能够减少线索诱导的恢复,啮齿动物
复发的相关性,以及这是否依赖于AMPK的激活。我们将确定颅内给药是否
伏核核心(NAcore)内的二甲双胍,这是一个已知的大脑区域,调节线索诱导的复发,
足以减少提示诱导的恢复训练的可卡因自我管理的大鼠。更重要的是,
我们将确定全身应用二甲双胍是否能有效减少复发率。
在恢复试验之前,颅内二甲双胍将被急性给药,全身二甲双胍将被
在禁欲期间长期给予,并进行灭绝训练。AMPK的药理或遗传抑制剂将是
用于探查二甲双胍对该激酶的依赖。同时磷酸化(活性)AMPK减少
在可卡因自身给药和消失后,急性可卡因或以下可卡因使磷酸化AMPK增加
一项提示诱导的复职测试。目标2将测试可卡因相关的AMPK活性诱导是否是一种
对限制奖励的补偿反应。我们假设观察到的活化的pAMPK的增加在
与线索诱导的恢复相关的NAcore与灭绝有关,而不是与寻求毒品有关。记忆
操作将用于区分线索消失和线索重新激活,PAMPK将在
纳科尔。最后,我们将评估为预激活AMPK而设计的二甲双胍预处理是否能够
抑制可卡因的获得自我给药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治疗干预措施的开发和
拓宽我们对可卡因易感性的分子机制的理解范围
旧病复发。
项目成果
期刊论文数量(0)
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{{ truncateString('SADE MONIQUE SPENCER', 18)}}的其他基金
Glutamatergic plasticity that drives cannabinoid withdrawal and craving
谷氨酸可塑性导致大麻素戒断和渴望
- 批准号:
10743526 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
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
- 批准号:
10593045 - 财政年份:2022
- 资助金额:
$ 23.25万 - 项目类别:
The role of dopamine in modulating relapse-induced transient synaptic plasticity
多巴胺在调节复发引起的瞬时突触可塑性中的作用
- 批准号:
9926487 - 财政年份:2018
- 资助金额:
$ 23.25万 - 项目类别:
The role of dopamine in modulating relapse-induced transient synaptic plasticity
多巴胺在调节复发引起的瞬时突触可塑性中的作用
- 批准号:
9751826 - 财政年份:2018
- 资助金额:
$ 23.25万 - 项目类别:
Role of Alpha2delta-1 in Cocaine Relapse and Gabapentin Mechanisms of Action
Alpha2delta-1 在可卡因复发中的作用和加巴喷丁的作用机制
- 批准号:
8839664 - 财政年份:2014
- 资助金额:
$ 23.25万 - 项目类别:
Role of Alpha2delta-1 in Cocaine Relapse and Gabapentin Mechanisms of Action
Alpha2delta-1 在可卡因复发中的作用和加巴喷丁的作用机制
- 批准号:
8716830 - 财政年份:2014
- 资助金额:
$ 23.25万 - 项目类别:
The role of dopaminergic transmission in the development of manic-like behaviors
多巴胺能传递在躁狂样行为发展中的作用
- 批准号:
7913994 - 财政年份:2010
- 资助金额:
$ 23.25万 - 项目类别:
The role of dopaminergic transmission in the development of manic-like behaviors
多巴胺能传递在躁狂样行为发展中的作用
- 批准号:
8111205 - 财政年份:2010
- 资助金额:
$ 23.25万 - 项目类别: