Graduation Date

Fall 12-15-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Integrative Physiology & Molecular Medicine

First Advisor

Gurudutt Pendyala

Abstract

The Opioid Epidemic has been a point of public health interest for the last twenty years. In this time, use of prescription opioids has grown exponentially, including use by pregnant women. The initial crisis has been focused on mitigating immediate problems such as lowering the significant loss of life in overdoses and providing support to cessation. Despite these advancements a separate phenomenon is on the rise: The rise in neonatal opioid withdrawal syndrome in neonatal care and associated challenges for these children as they age.

Currently preclinical research and epidemiological data suggests that exposed children are at risk for experiencing behavioral challenges. These sets of data also suggest children are at greater risk for developing substance abuse disorder later in life. Preclinically, data has demonstrated that deficits found in exposed offspring present significant global deficits early in life and to a degree the deficits are recoverable. However, our preclinical research is missing a key developmental window, adolescence. During adolescence children are highly susceptible to developing disorders and show the greatest amount of neurological and overall growth. This dissertation sought to fill this crucial gap in knowledge.

To address this gap in knowledge in this dissertation first provided a comprehensive characterization of perinatally opioid exposed (POE) offspring in two robust chronic preclinical models of opioid exposure: postnatal oxycodone exposure (PNO) and in utero oxycodone exposure (IUO). From these studies were found considerable phenotypic, synaptic, and behavioral deficits in the POE offspring. We also found, that PNO offspring were considerably more impacted. To elucidate possible mechanisms, we used RNA sequencing and pathway analyses. These studies found significant overlap between impacted genomes but also confirmed characterization that PNO-offspring displayed the greatest deficits. These studies further predicted offspring would be susceptible to nicotine exposure. This led us to hypothesis POE offspring would be more vulnerable to nicotine in early adolescence, subsequently exacerbating deficits. Finally, we sought to evaluate the impact of a novel does escalation approach of nicotine exposure in POE offspring. We performed a thorough characterization of offspring following exposure in late adolescence finding nicotine did not exacerbate differences found but did have interesting impacts on liver metabolism. Overall, the data here suggests that low dose nicotine, possibly stimulants, are safe therapeutics to treat POE offspring in adolescence and adulthood. This finding is crucial as offspring often experience disorders that are easily treated with low dose stimulants such as attention deficit disorder.

Comments

2023 Copyright, the authors

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