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毁灭性后果是， 由于滥用处方阿片类药物，美国怀孕妇女在过去20年中增加了一倍多 在此类案件中所占比例最大。这导致平均一个婴儿出生时就有新生儿。 每25分钟出现一次戒断综合症(NAS)。医护人员正在努力应对这场严重的危机 NAS以及对这些婴儿的长期健康后果。不足为奇的是，对生物多样性的基础研究 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 缺乏。PubMed对非人类“产前阿片类药物暴露”的搜索报告了自1976年以来发表的408篇文章， 在过去的10年里只有100个。我们的建议探索了一种新的想法，即产前接触羟考酮， 是最常见的处方阿片类药物之一，扰乱了中皮质边缘的正常发育 多巴胺奖赏系统通过异常的小胶质细胞激活和功能。比尔博医生最近 在大鼠身上证实，在青春期早期，伏隔核(NAC)的小胶质细胞是大脑的一个区域 对于奖励和厌恶是必要的，通过协调调节多巴胺D1受体(D1R)的表达 吞噬作用。这个过程是性别相关的，因为它选择性地发生在男性身上。她的团队还表明， 青春期吗啡激活小胶质细胞，扰乱小胶质细胞介导的D1R吞噬的正常过程， 增加了在子宫内接触阿片类药物可能会破坏小胶质细胞在发育过程中的活动的可能性， 从而导致终生动机行为的病理生理学。派·查托夫博士最近 证明雄性和雌性大鼠都学会了自我给药，这种处方阿片类药物经常被滥用， 羟考酮表现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 成年大鼠戒断吗啡后，NAC-D1R信号转导紊乱，自身反应增强 羟考酮的给药。总而言之，这份R21提案利用了新颖的发现和独特的技能 Chartoff和Bilbo实验室的一组来测试产前暴露于羟考酮的短期和 通过干扰小胶质细胞发育、小胶质细胞介导的吞噬作用对后代的长期影响 NAC中D1R的修剪，以及对阿片类药物奖赏相关影响的敏感性增加。我们将解决这一问题 两个目标的假设，这两个目标都将使用与临床相关的产前阿片类药物暴露模型 雌性大鼠在怀孕前和怀孕期间自我给药羟考酮。我们将检查产前的影响 羟考酮暴露对NAC早期小胶质细胞结构/功能及NAC D1Rs小胶质细胞清除的影响 出生后和后期(青春期)(目标1)和对羟考酮诱导的条件性位置的敏感性 青春期偏好(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和2)为R01拨款测试因果关系提供基础 胎儿期接触羟考酮的大鼠小胶质细胞功能障碍与成瘾行为易感性之间的关系。

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.