Prenatal oxycodone exposure: developmental effects on microglia and addiction-like behavior in rats

产前羟考酮暴露：对大鼠小胶质细胞和成瘾样行为的发育影响

基本信息

批准号：
10025577
负责人：
ELENA H CHARTOFF
金额：
$ 19.7万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10025577
关键词：
3-Dimensional Acute Addictive Behavior Address Adolescence Adolescent Adult Affect Basic Science Behavior Biological Birth Body Weight Body Weight decreased Brain Brain region Cell Count Cells Child Chronic Cognition Complement Data Development Dopamine Dopamine D1 Receptor Dose Drops Drug Kinetics Drug Modelings Drug usage Embryo Embryonic Development Exposure to Female Fostering Foundations Functional disorder Future Goals Grant Health Health Personnel Immune Infant Learning Life Link Long-Term Effects Longevity Male Adolescents Maternal Behavior Measures Mediating Messenger RNA Methods Microglia Modeling Modification Monitor Morphine Morphology Mothers Neonatal Abstinence Syndrome Neurobiology Nucleus Accumbens Opiate Addiction Opioid Outcome Oxycodone Partner in relationship Pathologic Pathway interactions Phagocytes Phagocytosis Pharmaceutical Preparations Play Pregnancy Pregnant Women Prevalence Process Proteins Psychopathology PubMed Public Health Publications Rattus Regulation Reporting Rewards Rodent Role Saline Self Administration Shapes Signal Transduction Structure Synapses System Testing Third Pregnancy Trimester Ultrasonics Weaning Withdrawal Woman Work addiction base chemokine clinically relevant conditioned place preference cytokine design dopamine system early adolescence fetal opioid exposure immune activation immune function macrophage male motivated behavior neural circuit neurobehavioral novel offspring opioid abuse opioid epidemic opioid exposure postnatal prenatal prenatal exposure prescription opioid abuse prescription opioid misuse pup reconstruction relapse risk response reward circuitry reward processing sex skills stem cells vocalization

3-Dimensional Acute Addictive Behavior Address Adolescence Adolescent Adult Affect Basic Science Behavior Biological Birth Body Weight Body Weight decreased Brain Brain region Cell Count Cells Child Chronic Cognition Complement Data Development Dopamine Dopamine D1 Receptor Dose Drops Drug Kinetics Drug Modelings Drug usage Embryo Embryonic Development Exposure to Female Fostering Foundations Functional disorder Future Goals Grant Health Health Personnel Immune Infant Learning Life Link Long-Term Effects Longevity Male Adolescents Maternal Behavior Measures Mediating Messenger RNA Methods Microglia Modeling Modification Monitor Morphine Morphology Mothers Neonatal Abstinence Syndrome Neurobiology Nucleus Accumbens Opiate Addiction Opioid Outcome Oxycodone Partner in relationship Pathologic Pathway interactions Phagocytes Phagocytosis Pharmaceutical Preparations Play Pregnancy Pregnant Women Prevalence Process Proteins Psychopathology PubMed Public Health Publications Rattus Regulation Reporting Rewards Rodent Role Saline Self Administration Shapes Signal Transduction Structure Synapses System Testing Third Pregnancy Trimester Ultrasonics Weaning Withdrawal Woman Work addiction base chemokine clinically relevant conditioned place preference cytokine design dopamine system early adolescence fetal opioid exposure immune activation immune function macrophage male motivated behavior neural circuit neurobehavioral novel offspring opioid abuse opioid epidemic opioid exposure postnatal prenatal prenatal exposure prescription opioid abuse prescription opioid misuse pup reconstruction relapse risk response reward circuitry reward processing sex skills stem cells vocalization

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项目摘要

One devastating consequence of the current opioid epidemic is that opioid abuse and dependence among pregnant women in the U.S. has more than doubled in the last 20 years, with the misuse of prescription opioids comprising the largest percentage of such cases. This has resulted in an average of one infant born with neonatal abstinence syndrome (NAS) every 25 minutes. Health care workers are struggling to handle the acute crisis of NAS as well as the long-term health consequences for these infants. Not surprisingly, basic research on the neurobiological effects of prenatal opioid exposure on brain development and motivated behavior is sorely lacking. A PubMed search of “prenatal opioid exposure” in non-humans reported 408 publications since 1976, with only 100 in the last 10 years. Our proposal explores the novel idea that prenatal exposure to oxycodone, one of the most commonly abused prescription opioids, disrupts normal development of the mesocorticolimbic dopamine reward system through aberrant microglia activation and function. Co-I Dr. Bilbo has recently demonstrated in rats that during early adolescence, microglia in the nucleus accumbens (NAc), a brain region necessary for reward and aversion, regulate dopamine D1 receptor (D1r) expression through coordinated phagocytosis. This process is sex-dependent, as it occurs selectively in males. Her group has also shown that adolescent morphine activates microglia and disrupts the normal process of microglia-mediated D1r engulfment, raising the possibility that in utero exposure to opioids could derail the actions of microglia during development, resulting in pathophysiologies in motivated behavior throughout the lifespan. PI Dr. Chartoff has recently demonstrated that both male and female rats learn to self-administer the commonly abused prescription opioid, oxycodone and show similar drug pharmacokinetics and dose response functions. Her group has also shown that morphine withdrawal in adult rats results in dysregulated NAc D1r signaling and increased self- administration of oxycodone. Taken together, this R21 proposal leverages the novel findings and unique skill sets of the Chartoff and Bilbo labs to test the hypothesis that prenatal oxycodone exposure has both short- and long-term effects on offspring through disruption of microglia development, microglia-mediated phagocytic pruning of D1rs in the NAc, and increased sensitivity to reward-related effects of opioids. We will address this hypothesis in two aims, both of which will use a clinically-relevant model of prenatal opioid exposure in which female rats self-administer oxycodone before and throughout pregnancy. We will examine the effects of prenatal oxycodone exposure on microglia structure/function and on microglial elimination of NAc D1rs in the NAc at early postnatal and later (adolescent) stages (Aim 1) and on sensitivity to oxycodone-induced conditioned place preferences in adolescence (Aim 2). These studies are designed to 1) expand our basic understanding of how opioids impact the developing brain and 2) provide the foundation for an R01 grant testing causal relationships between microglia dysfunction and vulnerability to addictive behavior in rats exposed prenatally to oxycodone.

当前阿片类药物流行的一个毁灭性后果是，阿片类药物滥用和依赖在过去的20年中，美国的孕妇增加了一倍以上，而对处方oioids则失误完成此类案件中最大的百分比。这平均有一个婴儿出生于新生儿每25分钟一次禁欲综合征（NAS）。卫生保健工作者正在努力应对急性危机 NAS以及这些婴儿的长期健康后果。毫不奇怪，关于产前阿片类药物暴露对脑发育和动机行为的神经生物学影响非常缺乏。自1976年以来，非人类的PubMed搜索“产前阿片类药物暴露”报告了408份出版物，在过去的10年中只有100个。我们的建议探讨了产前暴露于羟考酮的新颖想法，最常见的滥用处方阿片类药物之一破坏了中皮层的正常发育多巴胺奖励系统通过异常的小胶质细胞激活和功能。 Co-i Bilbo博士最近有在大鼠中证明，在青少年早期，伏隔核中的小胶质细胞（NAC），一个大脑区域对于奖励和厌恶所需的必要条件，通过协调调节多巴胺D1受体（D1R）表达吞噬作用。这个过程是性别依赖性的，因为它在男性中有选择地发生。她的小组还表明青少年吗啡激活小胶质细胞并破坏小胶质细胞介导的D1R吞噬的正常过程，提高子宫里接触阿片类药物的可能性可能使小胶质细胞在发育过程中的作用脱轨，在整个生命周期中导致动机行为的病理生理。 PI Chartoff博士最近有证明雄性和雌性大鼠都学会自我管理普遍滥用的处方oioid，羟考酮并显示相似的药物代动力学和剂量反应功能。她的小组也表明成年大鼠的吗啡戒断导致NAC D1R信号失调，自我增加氧气的给药。综上所述，该R21提案利用了新颖的发现和独特的技能 Chartoff和Bilbo实验室的集合，以检验以下假设：产前羟考酮暴露既短且小胶质细胞介导的小胶质细胞的破坏，对后代的长期影响 D1R在NAC中修剪，并提高对阿片类药物奖励相关作用的敏感性。我们将解决这个问题两个目标的假设，两者都将使用与临床上相关的产前阿片类药物暴露模型雌性大鼠在整个怀孕之前和整个怀孕之前和整个怀孕。我们将检查产前的影响在小胶质细胞结构/功能以及小胶质细胞消除NAC中NAC中NAC中NAC中的羟考酮暴露于早期产后及以后的（青少年）阶段（目标1）以及对羟考酮诱导的条件位置的敏感性青少年的偏好（AIM 2）。这些研究旨在1）扩展我们对如何 OPIOED会影响发育中的大脑，2）为R01赠款测试为因果关系提供了基础小胶质细胞功能障碍和在产前暴露于羟考酮的大鼠中添加行为的脆弱性之间。