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.

项目总结 随着阿片类药物使用障碍在孕妇中的流行程度上升，接触到 子宫内的阿片类药物急剧增加。尽管对阿片类药物对胎儿的影响知之甚少 开发、阿片类药物维持疗法，如美沙酮，是孕妇护理的标准。 有阿片类药物使用障碍。先前的研究表明，在怀孕期间接触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。尽管酒精是最有可能的 滥用药物这一不断增长的婴儿与胎儿阿片类药物接触将遇到和消费随着他们 据我们所知，还没有成熟的研究考察胎儿接触阿片类药物对饮酒模式的影响 或与酒精相关的神经行为适应。因为有问题的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，我们当务之急是 检查胎儿接触阿片类药物是否会使个人面临有问题的饮酒模式或AUD的风险。此外， 很少有研究研究与奖赏相关的大脑区域潜在的神经适应。 行为，如纹状体，这可能有助于这种增强的酒精奖励表型在胎儿阿片类药物 暴露的动物。为了解决这些未探索的问题，我们的实验室开发了一种可翻译的鼠标 寻求与人类阿片类药物暴露模式相似的模型，典型的第一个孕妇 怀孕前依赖羟考酮，然后进入美沙酮维持治疗计划，以及 随后在服用美沙酮的情况下怀孕。这个胎儿美沙酮的翻译模型 暴露(FME)产生的啮齿动物幼崽表现出与新生儿阿片类药物相似的临床症状 纳洛酮激发时的戒断综合征。此外，这些患有FME的幼崽表现出显著的 全脑含N2B的NMDA受体表达增加。该提案的中心目标是使用 本动物模型旨在探讨(1)FME是否改变了酒精诱导的行为适应和自愿性 饮酒模式；以及(2)FME是否在四个主要纹状体产生持续的神经适应 与对照动物相比，启动这些区域对酒精的不同反应的亚区。朝向 这个目标，目标1将检查酒精运动敏感化和酒精摄入量，利用酗酒 在有FME病史的青春期小鼠的黑暗模型中饮酒。在目标2中，全细胞膜片钳电生理 录音和定量Western blotting将用于表征谷氨酸的传递和谷氨酸 在自愿饮酒的不同阶段，FME小鼠的受体表达。作为一名 结果，预计我们的结果将有助于确定FME是否使个人倾向于未来的问题 饮酒行为可能有助于制定旨在预防或治疗AUD的策略 接触阿片类药物的婴儿人数不断增加。