Early Life Stress, Chronic Drug Use and Neuroplasticity in Nonhuman Primate Models of Cocaine Abuse: Relevance to Treatment Strategies

摘要 尽管青少年开始使用药物以终身成瘾的风险及其巨大的健康和 社会成本，导致对物质使用障碍（SUD）的脆弱性增加的神经生物学因素， 包括可卡因（COC）使用障碍（CUD），知之甚少。早期生活压力（ELS），包括不良 童年虐待（MALT）等经历，是SUD等精神病理学的主要风险因素， 焦虑和抑郁，这往往是共病。事实上，有童年MALT病史的人 更容易对COC成瘾，情绪调节的缺陷使他们更容易受到压力诱导 复发，导致吸毒螺旋上升。尽管存在这些风险，但ELS和COC在 青少年相互作用，改变大脑发育，增加了在以后的生活中对CUD的脆弱性， 阐明。从青春期开始使用药物的进展也有很大的性别差异 （实验）对药物依赖的发病，妇女表现出更大的脆弱性，虽然 潜在的神经生物学机制尚不清楚。本提案的目标是审查长期ELS- 相关的影响和神经生物学机制的风险增加，以CUD在成年期。为了实现这一点， 我们正在使用一种独特的、高度翻译的非人灵长类动物（NHP）婴儿MALT模型， 青少年COC自我管理（SA）和解决性别差异。这里提出的研究具有 在青春期经历婴儿MALT随后COC SA的成年猕猴队列，以及 自出生以来，纵向特征是无与伦比的。它们将提供与下列方面至关重要的信息： 人类健康大脑和儿童发育（HBCD）和青少年大脑认知发育 （ABCD）NIH研究通过检查SUD的早期风险因素和神经生物学机制。 这些研究利用这一独特的成年动物队列来研究ELS的长期影响 和青春期COC SA对奖励和压力/情绪调节电路的神经生物学，经过一年的 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， 前额叶皮层（PFC）与腹侧纹状体（中脑核）的功能连接（FC）， 杏仁核后再次暴露于COC SA（目的2），和DA和5-HT受体的恢复率， 长期COC戒断期间的FC，以研究其是否可预测COC诱导的复发， 对针对DA和5-HT受体的药物干预的反应; PET数据将告知 个性化医疗方法（目标3）。我们假设DA和5-HT受体的不同作用 化合物（单独与混合物）在MALT中的作用比对照动物大，并且在雌性动物中比雄性动物大。我们建议 ELS，除了青春期COC暴露外，还导致奖励和压力/情绪调节失调 系统通常报告在人类精神疾病，导致增加的风险，以CUD在成年期， 与青春期暴露于COC但无ELS史的动物进行比较。

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.