Oxycodone, Neonatal Opioid Withdrawal Syndrome, and Adult Abuse Liability

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The dramatic rise in opioid use and misuse over the past decade has resulted in an upsurge of infants born dependent upon opioids. Many of these babies will experience neonatal opioid withdrawal syndrome (NOWS) as their bodies withdraw from high levels of opioids in the maternal-fetal circulation. While there has been significant improvement in implementing and standardizing treatment protocols for managing NOWS infants, there remain significant concerns regarding the long-term impact of prenatal opioid exposure. Moreover it is unclear whether the severity of NOWS has any relationship with adult outcomes. Animal studies can be useful in identifying both potential long-term vulnerabilities as well as underlying changes in neurodevelopment that may confer increased risk. Preclinical data on prenatal oxycodone exposure are limited which is unfortunate given the widespread use of this particular opioid by women of reproductive age. We have recently developed an animal model of prenatal opioid exposure that utilizes self-administration of oxycodone with use beginning prior to conception and continuing throughout pregnancy. Our initial findings demonstrate dose-dependent changes in offspring body weight gain and ultrasonic vocalizations that emerge during the early postnatal period. In addition, we have documented significant changes in the transcriptional regulator MeCP2 on postnatal day 1 in these offspring. The current set of studies will determine whether brain region specific effects on MeCP2 persist across development and to what extent these effects are mediated by maternal intake and/or and postnatal withdrawal signs (Specific Aim 1). Studies will also determine the relationship between maternal intake, postnatal withdrawal signs and adult substance abuse liability and impulsive behavior, as these represent two potential vulnerabilities suggested in clinical findings (Specific Aim 2). Finally, these studies will determine whether similar outcomes are observed when females abruptly stop use during pregnancy (forced abstinence) or are transitioned from oxycodone to either methadone or buprenorphine, two common medications used in opioid replacement therapy (Specific Aim 3). Overall, these studies will determine the relationship between voluntary maternal intake of oxycodone, neonatal signs of withdrawal and long-term outcomes and test the hypothesis that these effects are due to epigenetic events induced by changes in MeCP2 expression.