Early Life Stress, Chronic Drug Use and Neuroplasticity in Nonhuman Primate Models of Cocaine Abuse: Relevance to Treatment Strategies
Early Life Stress, Chronic Drug Use and Neuroplasticity in Nonhuman Primate Models of Cocaine Abuse: Relevance to Treatment Strategies
批准号:
10380099
负责人:
Michael A Nader
金额:
$80.81万
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
项目状态:
未结题
起止时间:
2021-04-01 至 2026-01-31
关键词:
AbstinenceAddressAdolescenceAdolescentAdultAdverse eventAffectAgeAmygdaloid structureAnimalsAnxietyBehavioralBirthBrainBrain regionChild Abuse and NeglectChild DevelopmentChronicCocaineCocaine AbuseCocaine DependenceCocaine use disorderControl AnimalDataDevelopmentDiseaseDopamineDopamine ReceptorDrug AddictionDrug abuseDrug usageEffectivenessEmotional StressEmotionsFemaleFundingGoalsHealth Care CostsHeritabilityHumanIndividualIntakeInterventionLifeLongitudinal StudiesMacacaMacaca mulattaMagnetic Resonance ImagingMeasuresMental DepressionModelingMonkeysNational Institute of Drug AbuseNeurobiologyNeuronal PlasticityNucleus AccumbensPharmaceutical PreparationsPharmacologyPharmacology StudyPopulationPopulations at RiskPositron-Emission TomographyPrefrontal CortexProcessPsychological reinforcementPsychopathologyRecording of previous eventsRecoveryReinforcement ScheduleRelapseReportingResearchRewardsRiskRisk FactorsSerotoninSex DifferencesSocial statusStressSubstance Use DisorderSystemUnited States National Institutes of HealthVentral StriatumWomanaddictionbasecocaine exposurecocaine self-administrationcocaine usecognitive developmentcohortcomorbidityearly life stressemotion regulationexperiencefetal drug exposurein vivoinfant maltreatmentmalemaltreatmentneurobiological mechanismneuroimagingnonhuman primatenovelpersonalized medicineprospectivereceptorresearch studyresponseserotonin receptorsexsocietal coststreatment strategy
中文摘要
摘要
尽管青少年开始吸毒终生成瘾的风险及其巨大的健康和
社会成本,导致物质使用障碍(SUD)易感性增加的神经生物学因素,
包括可卡因(COC)使用障碍(CUD),人们对此知之甚少。早期生活压力(ELS),包括不利的
儿童期虐待(MALT)等经历是肥皂泡等精神疾病的主要风险因素,
焦虑和抑郁,这通常是并存的。事实上,有童年麦芽威士忌病史的人
更容易受到COC成瘾的影响,情绪调节缺陷使他们容易受到压力诱导
复发,助长了吸毒的螺旋式上升。尽管存在这些风险,ELS和COC在
青春期的相互作用改变了大脑的发育,增加了以后生活中对CUD的易感性,但还没有
已澄清。从青春期开始吸毒的进展也有很强的性别差异。
(实验)药物依赖的开始,女性表现出更多的脆弱性,尽管
潜在的神经生物学机制尚不清楚。这项建议的目标是审查长期ELS-
成年期CUD风险增加的相关影响和神经生物学机制。要做到这一点,
我们正在使用一种独特的、高度翻译的非人类灵长类(NHP)婴儿麦芽模型
青春期COC自我管理(SA)和解决性别差异。在这里提出的研究与一个
在青春期经历婴儿麦芽和COC SA的成年猕猴队列,以及
从出生起就具有纵向特征,是无与伦比的。它们将为以下方面提供至关重要的信息
人类健康脑与儿童发育(HBCD)与青少年脑认知发展
(ABCD)美国国立卫生研究院通过检查肥胖症的早期危险因素和神经生物学机制进行研究。
这些研究利用成年后这群独特的动物来研究ELS的长期影响。
和青春期COC SA关于奖赏和压力/情绪调节回路的神经生物学
COC戒断(目标1)、多巴胺(DA)和5-羟色胺(5-HT)受体的神经生物学变化以及
前额叶皮质(PFC)与腹侧纹状体(伏隔核)的功能联系
再暴露于COC SA后杏仁核(Aim 2),以及DA和5-HT受体的恢复率和
长期戒除COC期间的FC,以调查其是否预测COC诱导的复发和
针对DA和5-羟色胺受体的药物干预的反应;PET数据将提供信息
个性化医疗方法(目标3)。我们假设多巴胺和5-羟色胺受体的不同作用
麦芽中的化合物(单独与混合)比对照动物,在雌性与雄性中。我们建议
ELS,除了青春期COC暴露外,还会导致奖赏和压力/情绪的失调
通常在人类精神状况下报告的系统,导致成年后猝死的风险增加,
与有COC青春期暴露但没有ELS病史的动物进行比较。
英文摘要
Abstract
Despite the risks of adolescent initiation of drug use for lifelong addiction and its tremendous health and
societal costs, the neurobiological factors leading to increased vulnerability to substance use disorders (SUDs),
including cocaine (COC) use disorder (CUD), are poorly understood. Early life stress (ELS), including adverse
experiences such as childhood maltreatment (MALT), is a major risk factor for psychopathologies like SUDs,
anxiety and depression, which are often comorbid. Indeed, individuals with histories of childhood MALT are
more vulnerable to COC addiction, and deficits in emotional regulation predisposes them to stress-induced
relapse, contributing to spiraling of drug taking. Despite these risks, how ELS and COC abuse during
adolescence interact to alter brain development, increasing vulnerability to CUD later in life, has not been
elucidated. There are also strong sex differences in progression from initiation of drug use during adolescence
(experimentation) to the onset of drug dependence, with women showing increased vulnerability, although the
underlying neurobiological mechanisms are unclear. The goal of this proposal is to examine long-term ELS-
related impact and neurobiological mechanisms of increased risk to CUD during adulthood. To accomplish this,
we are using a unique and highly translational nonhuman primate (NHP) model of infant MALT with
adolescence COC self-administration (SA) and addressing sex differences. The studies proposed here with a
cohort of adult macaques that experienced infant MALT followed by COC SA during adolescence, and
characterized longitudinally since birth, are unparalleled. They will provide information of critical relevance for
the human HEALthy Brain and Child Development (HBCD) and Adolescent Brain Cognitive Development
(ABCD) NIH studies by examining early risk factors and neurobiological mechanisms for SUDs.
The studies leverage this unique cohort of animals during adulthood to examine the long-term impact of ELS
and adolescence COC SA on neurobiology of reward and stress/emotion regulatory circuits following a year of
COC abstinence (Aim 1), neurobiological changes in dopamine (DA) and serotonin (5-HT) receptors and
functional connectivity (FC) of prefrontal cortex (PFC) with ventral striatum (nucleus accumbens) and
amygdala following re-exposure to COC SA (Aim 2), and the rate of recovery of DA and 5-HT receptors and
FC during abstinence from long-term COC, to investigate whether it predicts COC-induced relapse and
responses to pharmacological interventions targeting DA and 5-HT receptors; PET data will inform
personalized medicine approaches (Aim 3). We hypothesize differential effectiveness of DA and 5-HT receptor
compounds (alone vs. mixtures) in MALT than Control animals, and in females versus males. We propose that
ELS, in addition to adolescence COC exposure, leads to the dysregulation of reward and stress/emotional
systems typically reported in human psychiatric conditions, resulting in increased risk to CUD in adulthood, in
comparison to animals with COC adolescence exposure but no ELS history.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys
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批准号:10765789
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项目类别:
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资助金额:$12.24万
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财政年份:2023
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负责人:Michael A Nader
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依托单位:
Early Life Stress, Chronic Drug Use and Neuroplasticity in Nonhuman Primate Models of Cocaine Abuse: Relevance to Treatment Strategies
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批准号:10552042
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资助金额:$80.87万
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Impact of In Utero Cocaine Exposure on Vulnerability to Drug Abuse in Monkeys.
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Impact of In Utero Cocaine Exposure on Vulnerability to Drug Abuse in Monkeys.
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资助金额:$35.29万
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Chronic Stress and Cocaine Abuse in Female Monkeys
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海外基金