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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

基本信息

批准号：
10676310
负责人：
Gregory Giovanni Grecco
金额：
$ 4.62万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/10676310
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 Darkness 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 chronic alcohol ingestion clinically relevant comparison control 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

项目摘要

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