The Impact of Fetal Methadone Exposure on Alcohol-Related Behavior and Alcohol-Induced Changes in the Striatum

项目摘要 随着孕妇中阿片类药物使用障碍的流行率增加， 子宫内的阿片类药物急剧增加。尽管关于阿片类药物对胎儿的影响的知识存在差距， 发展，阿片类药物维持疗法，如美沙酮，是孕妇的标准护理 阿片类药物使用障碍先前的研究表明，在妊娠期间暴露于阿片类药物的动物表现出 对阿片类药物和其他滥用药物的奖励表型增强。虽然酒精最有可能 滥用药物这一不断增长的婴儿人口与胎儿阿片类药物暴露将遇到和消费，因为他们 据我们所知，还没有研究探讨胎儿阿片类药物暴露如何影响饮酒模式 或酒精相关的神经行为适应。问题饮酒和酒精使用障碍（AUD） 与严重的发病率、死亡率以及社会和经济负担有关，我们必须 检查胎儿阿片类药物暴露是否会使个体处于有问题的饮酒模式或AUD的风险中。此外，委员会认为， 很少有研究调查了大脑中与奖赏相关的重要区域的潜在神经适应性 行为，如纹状体，这可能有助于胎儿阿片类药物中这种增强的酒精奖励表型 暴露的动物为了解决这些尚未探索的问题，我们的实验室开发了一种翻译小鼠， 该模型旨在模拟典型孕妇中阿片类药物暴露的人类模式， 妊娠前依赖羟考酮，然后进入美沙酮维持治疗计划， 随后在服用美沙酮期间怀孕。胎儿美沙酮的转化模型 暴露（FME）产生的啮齿动物幼崽表现出新生阿片样物质的临床病理学回忆 戒断综合征时，挑战与纳洛酮。此外，这些患有FME的幼仔显示出显著的 全脑含N2 B的NMDA受体表达增加。该提案的中心目标是利用 本研究旨在探讨（1）FME是否改变酒精诱导的行为适应和自愿行为， 饮酒模式;（2）如果FME在四个主要纹状体中产生持续的神经适应， 亚区域，其引发这些区域与对照动物相比对酒精的差异反应。朝向 为了达到这个目标，目标1将研究酒精运动敏感性和酒精摄入，利用酗酒， 在黑暗模型中饮酒的青少年小鼠与先前的FME。在目标2中，全细胞膜片钳电生理 记录和定量蛋白质印迹将用于表征谷氨酸传输和谷氨酸 受体表达，分别在不同阶段的自愿饮酒FME小鼠。作为 结果，预计我们的研究结果将有助于确定FME是否会使个人未来出现问题 饮酒行为，这可能有助于制定旨在预防或治疗AUD的策略， 阿片类药物暴露的婴儿人数不断增加。

PROJECT SUMMARY As the prevalence of opioid use disorder in pregnant women has grown, the number of neonates exposed to opioids in utero has risen sharply. Despite the gap in knowledge regarding the impact of opioids on fetal development, opioid maintenance therapies, such as methadone, are the standard of care for pregnant women with opioid use disorder. Prior studies have shown that animals exposed to opioids during gestation demonstrate an enhanced reward phenotype to opioids and other abused drugs. Although alcohol represents the most likely abused drug this growing population of infants with fetal opioid exposure will encounter and consume as they mature, no studies to our knowledge have examined how fetal opioid exposure impacts alcohol drinking patterns or alcohol-related neurobehavioral adaptations. Because problematic drinking and alcohol use disorder (AUD) is associated with significant morbidity, mortality, and social and economic burden, it is imperative that we examine if fetal opioid exposure puts individuals at risk for problematic drinking patterns or AUD. Furthermore, few studies have investigated underlying neuroadaptations in brain regions important for reward related behavior, such as the striatum, which may contribute to this enhanced alcohol reward phenotype in fetal opioid exposed animals. To address these unexplored questions, our laboratory has developed a translational mouse model that seeks to resemble human patterns of opioid exposure in a typical pregnant woman who is first dependent on oxycodone prior to gestation, then enters a methadone maintenance therapy program, and subsequently becomes pregnant while maintained on methadone. This translational model of fetal methadone exposure (FME) produces rodent pups which exhibit clinical symptomology reminiscence of neonatal opioid withdrawal syndrome when challenged with naloxone. Furthermore, these pups with FME display significantly increased expression of whole-brain N2B-containing NMDA receptors. The central goal of the proposal is to use this animal model of FME to explore (1) if FME alters alcohol-induced behavioral adaptations and voluntary alcohol drinking patterns; and (2) if FME produces persistent neuroadaptations in the four major striatal subregions which primes these regions to differentially respond to alcohol compared to control animals. Towards this goal, Aim 1 will examine alcohol locomotor sensitization and alcohol intake, utilizing the binge-alcohol drinking in the dark model in adolescent mice with prior FME. In Aim 2, whole cell patch clamp electrophysiology recordings and quantitative western blotting will be used to characterize glutamate transmission and glutamate receptor expression, respectively, in mice with FME following different stages of voluntary alcohol drinking. As a result, it is expected that our results will help to determine if FME predisposes individuals to future problematic alcohol drinking behavior which may aid in developing strategies aimed at preventing or treating AUD in this growing population of opioid exposed infants.