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

目前阿片类药物流行的一个破坏性后果是， 在过去的20年里，美国孕妇滥用处方阿片类药物的人数增加了一倍多。 占此类案件的最大比例。这导致平均一名新生儿出生时 戒断综合征（NAS）每25分钟。卫生保健工作者正在努力处理严重的危机， NAS以及对这些婴儿的长期健康后果。毫不奇怪，对人类的基础研究 产前阿片类药物暴露对大脑发育和动机行为的神经生物学影响非常严重， 缺乏自1976年以来，PubMed对非人类“产前阿片类药物暴露”的搜索报告了408篇出版物， 在过去的十年里只有100个。我们的提案探索了一个新颖的想法，产前接触羟考酮， 最常滥用的处方阿片类药物之一，破坏了中皮质边缘的正常发育， 多巴胺奖励系统通过异常的小胶质细胞激活和功能。比尔博博士最近 在大鼠中证明，在青春期早期，脑区中脑核（NAc）中的小胶质细胞 必要的奖励和厌恶，调节多巴胺D1受体（D1 r）的表达，通过协调 吞噬作用这个过程是依赖于性别的，因为它选择性地发生在男性身上。她的研究小组还表明， 青少年吗啡激活小胶质细胞并破坏小胶质细胞介导的D1 r吞噬的正常过程， 增加了子宫内暴露于阿片类药物可能会破坏小胶质细胞在发育过程中的作用的可能性， 导致整个生命周期中的动机行为的病理生理学。PI Chartoff博士最近 表明雄性和雌性大鼠都学会了自我管理通常滥用的处方阿片类药物， 羟考酮和羟考酮显示出相似的药物药代动力学和剂量反应函数。她的团队还展示了 成年大鼠吗啡戒断导致NAc D1 r信号失调， 给药羟考酮。综上所述，R21建议利用了新的发现和独特的技能， Chartoff和Bilbo实验室的一组实验室，以检验产前羟考酮暴露既有短期， 通过破坏小胶质细胞发育、小胶质细胞介导的吞噬作用 修剪的D1 rs在NAc，并增加敏感性阿片类药物的奖励相关的影响。我们会解决这个问题 两个目标的假设，这两个目标都将使用产前阿片类药物暴露的临床相关模型，其中 雌性大鼠在怀孕前和整个怀孕期间自我施用羟考酮。我们将研究产前检查的影响 羟考酮暴露对小胶质细胞结构/功能和早期NAc中NAc D1 rs的小胶质细胞消除的影响 出生后和后期（青少年）阶段（目的1）以及对羟考酮诱导的条件性位置的敏感性 青春期的偏好（目标2）。这些研究的目的是：1）扩大我们对 阿片类药物影响发育中的大脑，2）为R 01赠款测试因果关系提供基础 产前暴露于羟考酮的大鼠中小胶质细胞功能障碍与成瘾行为的脆弱性之间的关系。

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.