MODELING MATERNAL OPIOID USE DISORDER AND ITS CONSEQUENCES IN MICE OFFSPRING

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Neuroscience
Discipline
Neuroscience and Neurobiology
Subject
ethanol
morphine
mouse
neonatal opioid withdrawal syndrome
neonate
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Copyright date
2022
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Author
Fleites, Vanessa, Caridad
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Abstract

The opioid epidemic has seen an increase in drug use among women of reproductive age. Opioid Use Disorder can have many negative consequences for the health of pregnant mothers and their babies, but our understanding of the impact of fetal opioid exposure on behavior during adolescence and adulthood is less understood. Preclinical studies have unveiled some of the long-term effects of in utero morphine exposure primarily using injections, osmotic minipumps, and forced oral opioid drinking as the route of drug delivery. This dissertation presents a collection of experiments using a (i) prenatal-perinatal and (ii) prenatal-preweaning morphine exposure paradigm to describe the effects on neonate, adolescent, and adult offspring behavior. First, we validated a paradigm where female mice first became morphine dependent pre-pregnancy, then continued to consume morphine in a continuous two-bottle choice (2BC) paradigm during pregnancy and up to offspring postnatal day (PND) 7, at which point offspring were cross-fostered (prenatal-perinatal), or up to offspring PND 21 (prenatal-preweaning). We demonstrated that morphine dams display signs of dependence and voluntarily drink morphine throughout gestation.Offspring exposed to prenatal-perinatal morphine displayed changes in neonate outcomes, including ultrasonic vocalization parameters. They also showed changes in anxiety-like behavior, ethanol intake before and after an acute stressor, and a greater percentage of them had more severe global behavioral scores. Next, we demonstrated that offspring exposed to morphine prenatally and up to the time of weaning display changes in adolescent behavior, including alterations in preference for nicotine in a 2BC, transcriptomic changes in the Prefrontal Cortex, and an increased proportion of offspring classifying in the more severe behavioral phenotypes. During adulthood, the same offspring displayed differences in behavioral phenotype classification, and changes in ethanol intake and/or preference in an intermittent 2BC paradigm and a binge-like drinking procedure. Overall, prenatal-perinatal and prenatal-preweaning morphine exposure leads to subtle sex-specific changes in neonatal, adolescent, and adult behavior. Altogether, this body of work contributes to the current understanding of the effects of in utero opioid exposure and potential vulnerable/resilient populations among offspring.

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De Biasi, Mariella
Date of degree
2022
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