Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Pregnancy is a critical period for brain development, and drug use during this time disrupts ontogenic trajectories. During the last decade, the use of prescription opioids during pregnancy has reached notably high rates (14- 22%) in the United States. While previous research has focused on the offspring for in utero effects of opioid use, the impact on the mother’s postpartum mental health has been largely overlooked. Notably, drug overdoses are one of the main preventable causes of pregnancy-related deaths, mainly occurring in this period. Here, we will assess the neurobehavioral changes caused by prescription opioid exposure during pregnancy and their postpartum impact on drug reward. The proposed work will focus on two key at-risk mechanisms during pregnancy: oxytocin and dopamine. Central oxytocin signaling by paraventricular hypothalamic neurons (PVNOXT) is halted during pregnancy and quickly re-initiated after parturition. Upon resumption of oxytocin release, ventral tegmental area (VTA)-projecting PVNOXT neurons promote attribution of incentive value to salient stimuli (e.g., pups). Therefore, VTA-projecting PVNOXT, which express µ-opioid receptors (µOR), represent a substrate for the pharmacological actions of prescription opioids (such as oxycodone) during pregnancy. We hypothesize that repeated activation of PVNOXT µOR leads to opioid tolerance and a long-term loss of inhibitory control over PVNOXT excitability, hence exacerbating VTA oxytocin release and altering dopamine function postpartum. We will use drug self-administration and neuroeconomic modeling to profile postpartum vulnerability to drug abuse in dams exposed to prescription opioids during pregnancy. Additionally, we will employ fiber photometry to examine in vivo changes in dopamine and oxytocin encoding of opioid rewards and electrophysiological tools to characterize PVNOXT synaptic alterations. Finally, optogenetic manipulations will address the sufficiency of the PVNOXT→VTA pathway to gate augmented postpartum reward-seeking behaviors in opioid-naïve mice. Together, these experiments will uncover novel behavioral and neural circuit aberrations resulting from prescription opioid exposure during pregnancy, focusing on the dam’s vulnerability to postpartum opioid abuse. Ultimately, this research proposal seeks to uncover a potential neurobiological mechanism linking the increased use of prescription opioids during pregnancy and the rise in postpartum overdose deaths.
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