One devastating consequence of the current opioid epidemic is that opioid abuse and dependence among pregnant women in the U.S. has more than doubled in the last 20 years, with the misuse of prescription opioids comprising the largest percentage of such cases. This has resulted in an average of one infant born with neonatal abstinence syndrome (NAS) every 25 minutes. Health care workers are struggling to handle the acute crisis of NAS as well as the long-term health consequences for these infants. Not surprisingly, basic research on the neurobiological effects of prenatal opioid exposure on brain development and motivated behavior is sorely lacking. A PubMed search of ?prenatal opioid exposure? in non-humans reported 408 publications since 1976, with only 100 in the last 10 years. Our proposal explores the novel idea that prenatal exposure to oxycodone, one of the most commonly abused prescription opioids, disrupts normal development of the mesocorticolimbic dopamine reward system through aberrant microglia activation and function. Co-I Dr. Bilbo has recently demonstrated in rats that during early adolescence, microglia in the nucleus accumbens (NAc), a brain region necessary for reward and aversion, regulate dopamine D1 receptor (D1r) expression through coordinated phagocytosis. This process is sex-dependent, as it occurs selectively in males. Her group has also shown that adolescent morphine activates microglia and disrupts the normal process of microglia-mediated D1r engulfment, raising the possibility that in utero exposure to opioids could derail the actions of microglia during development, resulting in pathophysiologies in motivated behavior throughout the lifespan. PI Dr. Chartoff has recently demonstrated that both male and female rats learn to self-administer the commonly abused prescription opioid, oxycodone and show similar drug pharmacokinetics and dose response functions. Her group has also shown that morphine withdrawal in adult rats results in dysregulated NAc D1r signaling and increased self- administration of oxycodone. Taken together, this R21 proposal leverages the novel findings and unique skill sets of the Chartoff and Bilbo labs to test the hypothesis that prenatal oxycodone exposure has both short- and long-term effects on offspring through disruption of microglia development, microglia-mediated phagocytic pruning of D1rs in the NAc, and increased sensitivity to reward-related effects of opioids. We will address this hypothesis in two aims, both of which will use a clinically-relevant model of prenatal opioid exposure in which female rats self-administer oxycodone before and throughout pregnancy. We will examine the effects of prenatal oxycodone exposure on microglia structure/function and on microglial elimination of NAc D1rs in the NAc at early postnatal and later (adolescent) stages (Aim 1) and on sensitivity to oxycodone-induced conditioned place preferences in adolescence (Aim 2). These studies are designed to 1) expand our basic understanding of how opioids impact the developing brain and 2) provide the foundation for an R01 grant testing causal relationships between microglia dysfunction and vulnerability to addictive behavior in rats exposed prenatally to oxycodone.
The prevalence of opioid abuse and dependence among pregnant women is skyrocketing, and neither the immediate nor long-lasting effects on brain development and behavior are understood. Microglia are a class of resident immune cells in the brain that not only protect the brain from early life insults, but also play an essential role in sculpting neural circuits such as the mesocorticolimbic dopamine system that ultimately control reward processing and motivated behavior. The goal of the proposed studies is to test the hypothesis that prenatal exposure to oxycodone, a commonly abused opioid, causes both acute and long-lasting disruptions in microglia function and microglia-mediated pruning of dopamine D1 receptors within the mesocorticolimbic dopamine system and subsequent disruptions in behavior in male and female offspring.
