Lasting Neurological Effects of Perinatal Opioids

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Project Summary Opioid use, dependence, and addiction have increased to epidemic proportions in recent years, leading to substantial financial and societal health burdens. More than 20% of pregnant women enrolled in Medicaid are prescribed opioids; In recent years there was a 14-fold increase in the proportion of pregnant women self- reporting opioid abuse. As a result, the incidence of infants born to opioid-using mothers has increased >400% between 2000 and 2012. These newborns are often treated with opioids, further increasing their exposure to these substances. Infants with intrauterine exposure to opioids have an increased risk for neurodevelopmental problems or adverse sensory, cognitive, psychomotor, and behavioral outcomes, negative outcomes that last through childhood, and likely throughout life. Currently, there is virtually no information regarding neural-circuit adaptations occurring in with opioid exposure during early life. We developed a mouse model in which animals are treated with fentanyl during a period corresponding to human gestation. These mice display lasting alterations in emotional behaviors that are specific to sex. Adolescent males exposed to perinatal fentanyl show enhanced anxiety-like behavior, while adolescent females show reduced motivation. Our studies will investigate alterations in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) circuitry known to be involved in these emotional behaviors. We will investigate cellular, plasticity, and molecular adaptations in mPFC and NAc cell subtypes in perinatal fentanyl exposed mice at early post weaning until adolescence. We will target identified molecular adaptations in distinct cell subtypes to determine their role in circuit and emotional behavioral disruptions occurring with perinatal fentanyl exposure. Our studies will, for the first time, uncover cellular, circuit, and molecular adaptations occurring after perinatal exposure to fentanyl and determine the circuitry mediating the long lasting neurobiological anomalies that occur with perinatal opioid exposure.