Date of Award

2022

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. W. Christopher Risher, Committee Chairperson

Second Advisor

Dr. Richard Egleton

Third Advisor

Dr. Philippe Georgel

Fourth Advisor

Dr. Brandon Henderson

Fifth Advisor

Dr. Mary Payne

Abstract

One of the most significant outcomes of the rise in rates of opioid abuse in the United States has been a dramatic increase in the incidence of neonatal abstinence syndrome (NAS), the clinical diagnosis for the collection of withdrawal-like signs and symptoms commonly observed in the newborns of mothers who abused certain drugs, such as opioids, during pregnancy. While a great deal of research has investigated the short-term symptoms and potential treatments for NAS, including my own studies to identify emerging trends among a local population of NAS patients, there remains a critical need to investigate the long-term effects of prenatal drug exposure on neurological development. A potential route through which drugs of abuse likely interact with the developing nervous system lies in astrocyte-mediated synaptic development, more specifically in signaling involving thrombospondins, a class of astrocyte secreted glycoproteins that act through binding to the neuronal cell surface receptor α2δ-1. α2δ-1 is also the receptor for the antiepileptic drug gabapentin. Co-abuse of opioids and gabapentin during pregnancy is associated with a unique presentation of NAS. I have therefore hypothesized that prenatal exposure to drugs of abuse leads to significant disruptions in astrocyte mediated synaptogenic signaling, resulting in permanent deficits in synapse formation and alterations in behaviors associated with addiction. To test this, I treated pregnant mice transgenic for α2δ-1 with one of four treatments: the opioid drug buprenorphine, gabapentin, a combination of both drugs, or a vehicle control. α2δ-1 wild-type, heterozygous, and knockout littermate pups of both sexes at 21 days of age were used for studies involving immunohistochemistry and confocal fluorescence microscopy to investigate synaptic connectivity within brain regions associated with reward. A second cohort of pups at 70 days of age underwent the same studies after first undergoing behavioral experiments examining anxiety, locomotion, and reward seeking. By completing these studies, I hoped to contribute to a greater understanding of the effects of prenatal opioid exposure on neurological and behavioral development that would inform parents, healthcare providers, and educators looking to meet the unique developmental and educational needs of children impacted by drug abuse.

Subject(s)

Opioids – Receptors – Research.

Opioids – Side effects.

Pediatric neurology – Research.

Astrocytes.

Synapses.

Download

Share

COinS