Preventing alcohol seeking with a nonmuscle myosin II inhibitor under clinical development
使用临床开发中的非肌肉肌球蛋白 II 抑制剂预防酗酒
基本信息
- 批准号:10405046
- 负责人:
- 金额:$ 19.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAlcohol consumptionAlcohol dependenceAlcoholsAmphetaminesAmygdaloid structureAnimalsApplications GrantsAssociation LearningBehaviorBrain regionClinicClinicalClinical TreatmentCocaineComplexCuesCytoskeletal ModelingCytoskeletonDataDendritic SpinesDevelopmentDisulfiramDoseFoodFoundationsFundingFutureGeneticHomeInvestigationLearningLiteratureMediatingMemoryMethamphetamineMethamphetamine use disorderMissionModelingMorphineMotivationMyosin Type IINaltrexoneNational Institute on Alcohol Abuse and AlcoholismNatureNicotinePatientsPersonsPharmaceutical PreparationsPharmacologyPhase I Clinical TrialsPrevention approachPropertyProteinsRelapseResearchRetrievalRewardsRisk FactorsRoleSelf AdministrationSpecificityStimulusStructureSubstance Use DisorderSynaptic plasticityTestingTherapeuticTimeTrainingTranslationsUnited States National Institutes of HealthVertebral columnWorkacamprosatealcohol cuealcohol effectalcohol preventionalcohol relapsealcohol seeking behavioralcohol use disorderbaseclinical developmentconditioned place preferencedepolymerizationdisorder later incidence preventiondrug of abusefear memoryinhibitormephedronemethamphetamine exposuremultidrug abusenon-muscle myosinnovelnovel therapeutic interventionnovel therapeuticspolymerizationpostsynapticpreventpublic health relevancerelapse riskspatial memorytherapeutic target
项目摘要
PROJECT SUMMARY
While several medications have been approved for alcohol use disorder (AUD), many patients fail to respond
or comply with the treatments. Relapse triggered by reminders of alcohol use is a particular challenge to
prevent, as the underlying memories exert a powerful motivational influence over behavior and represent a
lifelong relapse risk factor. Learning of these associations is supported by structural plasticity in dendritic
spines, driven by training-induced actin polymerization. Memory stability is subsequently achieved by arresting
actin dynamics, stabilizing the cytoskeleton. As a result, memory is impervious to actin depolymerization within
minutes of learning. However, prior work in the lab discovered that the actin cytoskeleton supporting
methamphetamine and amphetamine memories remains uniquely dynamic in the amygdala long after training.
This enables selective, retrieval-independent disruption of these memories and associated drug seeking with a
single administration of an actin depolymerizer. Because actin’s critical roles in the body limit its therapeutic
potential, focus shifted to nonmuscle myosin II (NMII), a direct driver of learning-stimulated actin polymerization
in spines. Genetic and pharmacologic targeting of NMII established it is a viable therapeutic target and an NIH-
funded medication development project for a clinically safe NMII inhibitor is underway, currently at the stage of
IND-enabling studies (UH3 NS096833). The central hypothesis in the current proposal is that a single
administration of an NMII inhibitor will produce a long-lasting disruption of alcohol seeking. Aim 1 will
determine the retrieval-independent ability of NMII inhibition to disrupt associations that trigger alcohol seeking,
like methamphetamine and amphetamine. Interestingly, the retrieval-independent effect of NMII inhibition does
not extend to memories for fear, food, spatial memory or several other drugs of abuse. However, it does
disrupt the reconsolidation of memories associated with drugs of abuse, including cocaine. Aim 2 will test the
effect of NMII inhibition on reconsolidation of alcohol-associated memories and seeking. However, the
relatively unique approach of reactivating memory with the unconditioned stimulus (US; a small amount of
alcohol), rather than the conditioned stimuli (CS; associated context and cues) will be utilized. This US-based
approach circumvents the limitation inherent to CS-based reactivation strategies, which require that potentially
hundreds of associations be recalled in a clinical setting to enable disruption. As proof-of-principle, preliminary
data indicate that US-based reactivation renders cocaine (COC)-associated memory susceptible to NMII
inhibition. The proposed work is expected to identify a new therapeutic approach to the prevention of relapse to
alcohol seeking with the potential for rapid translation through the use of a first in class compound whose NIH-
funded development is on track for FDA approval. Importantly, the proposed studies will also lay the
groundwork for an in depth mechanistic investigation in a subsequent R01.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Central amygdala CRF1 cells control nociception and anxiety-like behavior.
中央杏仁核 CRF1 细胞控制伤害感受和焦虑样行为。
- DOI:10.1038/s41386-023-01693-2
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Weera,MarcusM;Gilpin,NicholasW
- 通讯作者:Gilpin,NicholasW
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NICHOLAS WARREN GILPIN其他文献
NICHOLAS WARREN GILPIN的其他文献
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{{ truncateString('NICHOLAS WARREN GILPIN', 18)}}的其他基金
8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain
8/8 NADIA U01 青少年酒精对疼痛的长期影响
- 批准号:
10473652 - 财政年份:2020
- 资助金额:
$ 19.77万 - 项目类别:
8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain
8/8 NADIA U01 青少年酒精对疼痛的长期影响
- 批准号:
10671490 - 财政年份:2020
- 资助金额:
$ 19.77万 - 项目类别:
8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain
8/8 NADIA U01 青少年酒精对疼痛的长期影响
- 批准号:
10227251 - 财政年份:2020
- 资助金额:
$ 19.77万 - 项目类别:
8/8 NADIA U01 Long-Term Effects of Adolescent Alcohol on Pain
8/8 NADIA U01 青少年酒精对疼痛的长期影响
- 批准号:
10074983 - 财政年份:2020
- 资助金额:
$ 19.77万 - 项目类别:
Travel Support for the 7th International Drug Abuse Research Society (IDARS) Meeting
第七届国际药物滥用研究协会 (IDARS) 会议的差旅支持
- 批准号:
10625848 - 财政年份:2019
- 资助金额:
$ 19.77万 - 项目类别:
Travel Support for the 7th International Drug Abuse Research Society (IDARS) Meeting
第七届国际药物滥用研究协会 (IDARS) 会议的差旅支持
- 批准号:
10207352 - 财政年份:2019
- 资助金额:
$ 19.77万 - 项目类别:
Travel Support for the 7th International Drug Abuse Research Society (IDARS) Meeting
第七届国际药物滥用研究协会 (IDARS) 会议的差旅支持
- 批准号:
9761756 - 财政年份:2019
- 资助金额:
$ 19.77万 - 项目类别:
Travel Support for the 7th International Drug Abuse Research Society (IDARS) Meeting
第七届国际药物滥用研究协会 (IDARS) 会议的差旅支持
- 批准号:
10443761 - 财政年份:2019
- 资助金额:
$ 19.77万 - 项目类别:
Travel Support for the 7th International Drug Abuse Research Society (IDARS) Meeting
第七届国际药物滥用研究协会 (IDARS) 会议的差旅支持
- 批准号:
9980237 - 财政年份:2019
- 资助金额:
$ 19.77万 - 项目类别:
Generation and validation of a CRFR1-cre transgenic rat to study alcohol dependence
用于研究酒精依赖的 CRFR1-cre 转基因大鼠的生成和验证
- 批准号:
9761939 - 财政年份:2018
- 资助金额:
$ 19.77万 - 项目类别:
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