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

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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.