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

胎儿美沙酮暴露对酒精相关行为和酒精引起的纹状体变化的影响

• 批准号: 10473710
• 负责人: Gregory Giovanni Grecco
• 金额: $ 4.52万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473710
• 关键词: AMPA Receptors; Acute; Address; Adolescent; Age; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Animals; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Cells; Clinical; Cocaine; Consumption; Control Animal; Corpus striatum structure; Data; Development; Doctor of Philosophy; Dorsal; Economic Burden; Electrophysiology (science); Environment; Exhibits; Exposure to; Fetal Development; Future; Glutamate Receptor; Glutamates; Goals; High Prevalence; Homeostasis; Human; Individual; Infant; Knowledge; Laboratories; Laboratory Study; Life; Lifestyle-related condition; Literature; Mediating; Mentorship; Methadone; Methamphetamine; Modeling; Morbidity - disease rate; Motor; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Naloxone; Neonatal Abstinence Syndrome; Neurobiology; Neurons; Newborn Infant; Nucleus Accumbens; Opioid; Opioid replacement therapy; Oxycodone; Pathway interactions; Pattern; Phenotype; Physicians; Physiology; Play; Population; Pregnancy; Pregnant Women; Prevalence; Prevention strategy; Procedures; Rewards; Risk; Rodent; Saline; Scientist; Structure; Testing; Time; Training; Up-Regulation; Western Blotting; alcohol availability; alcohol behavior; alcohol exposure; alcohol research; alcohol response; alcohol reward; alcohol risk; alcohol seeking behavior; alcohol sensitivity; alcohol use disorder; base; chronic alcohol ingestion; clinically relevant; drinking; drinking behavior; drug of abuse; drug reward; fetal; fetal opioid exposure; improved; in utero; innovation; methadone treatment; mortality; mouse model; neonate; neuroadaptation; neurobehavioral; opioid exposure; opioid use disorder; opioid use in pregnancy; patch clamp; postnatal; pre-doctoral; pregnant; prescription opioid; prevent; programs; pup; receptor expression; social; standard of care; targeted treatment; therapeutic target; translational model; transmission process

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.

项目摘要 随着孕妇阿片类药物使用障碍的患病率的增加，接触的新生儿数量 子宫里的阿片类药物急剧上升。尽管知识差距有关阿片类药物对胎儿的影响 开发，阿片类药物维持疗法，例如美沙酮，是孕妇的护理标准 与阿片类药物使用障碍。先前的研究表明，妊娠期间暴露于阿片类药物的动物证明 对阿片类药物和其他滥用药物的奖励表型增强。虽然酒精代表最有可能的 滥用药物，越来越多的胎儿阿片类药物暴露的婴儿将遇到和消费 成熟，据我们所知，没有研究胎儿阿片类药物暴露如何影响饮酒方式 或与酒精有关的神经行为适应。因为饮酒和饮酒障碍（AUD） 与巨大的发病率，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是否会使个人有问题的饮酒方式或AUD的风险。此外， 很少有研究研究大脑区域中对奖励相关的重要神经适应 行为，例如纹状体，可能有助于这种增强的胎儿阿片类酒精奖励表型 暴露的动物。为了解决这些未开发的问题，我们的实验室已经开发了翻译鼠标 试图像典型的孕妇中类似于人类阿片类药物暴露模式的模型 妊娠前取决于羟考酮，然后进入美沙酮维持治疗计划，并 随后在美沙酮上保持怀孕。这种胎儿美沙酮的翻译模型 暴露（FME）产生啮齿动物幼崽，表现出新生儿阿片类药物的临床症状回忆 戒断综合征在用纳洛酮挑战时。此外，这些带有FME的幼崽显示出明显的显示 增加含N2B NMDA受体的全脑表达增加。该提案的核心目标是使用 如果FME改变了酒精诱导的行为适应和自愿性，则可以探索FME的动物模型（1） 饮酒方式； （2）如果FME在四个主要纹状体中产生持续的神经适应 与对照动物相比，这些区域差异差异的子区域对酒精有差异反应。向 AIM 1将利用暴饮暴食，AIM 1检查酒精运动敏化和酒精摄入量 先前FME的青少年小鼠中的黑暗模型中的饮酒。在AIM 2中，全细胞贴片夹电生理学 记录和定量蛋白质印迹将用于表征谷氨酸传播和谷氨酸 在自愿饮酒的不同阶段，在具有FME的小鼠中分别在受体表达。作为 结果，预计我们的结果将有助于确定FME是否使个人易于有问题 饮酒行为可能有助于制定旨在防止或治疗AUD的策略 不断增长的阿片类药物暴露婴儿。