PHD, Kent State University, 2024, College of Arts and Sciences / School of Biomedical Sciences
As of 2022, three million people in the US, and sixteen million worldwide were estimated to suffer from opioid use disorder (OUD). Despite widespread efforts to increase the public availability of medical therapies for OUD, only 2.28% of people suffering from OUD will seek out and be able to sustain abstinence for at least five years. The core objectives of this work were to 1) evaluate the dose- and sex-dependent effects of fentanyl to induce rewarding states, 2) the extent to which D-Cysteine ethylester (D-CYSee) alters affective state and the acquisition of fentanyl-induced reward seeking, 3) how the timing and concentration of fentanyl administration impacts the intrinsic Ca2+ activity of neurons and astroglia from the prefrontal cortex (PFC), and 4) the extent to which D-CYSee alters intrinsic Ca2+ activity in both the presence and absence of fentanyl. To evaluate the effects of fentanyl in the presence and absence of D-CYSee on Ca2+ signaling dynamics in PFC neurons and astrocytes, this work details the development of new methods in real-time fluorescent imaging of intrinsic Ca2+ activity using a non-genetic chemical indicator in cells isolated from the rat PFC in combination with post-hoc live-cell labeling for neurons and astroglia, and a customizable cell-type informed statistical analysis pipeline with backend support for data visualization and meta-analysis. Furthermore, a general characterization of the intrinsic Ca2+ activity in this PFC preparation was conducted; first by examining the involvement of extracellular Ca2+ sources and sodium channel conductance's, followed by a deeper evaluation of the role(s) of voltage-gated L, T, & N/P/Q-Type Ca2+ channels and an assessment of NMDA, AMPA receptor, and GABAA receptor signaling in the expression of intrinsic Ca2+ activity. The findings here support: 1) that fentanyl induces reward seeking in a concentration- and sex-dependent manner, 2) that D-CYSee could be an effective co-treatment with prescribed opioi (open full item for complete abstract)
Committee: Devin Mueller, Ph.D. (Advisor); Derek S. Damron, Ph.D. (Advisor); Stephen J. Lewis, Ph.D. (Committee Member); Colleen Novak, Ph.D. (Committee Member); Robert Clements, Ph.D. (Committee Member); Rafaela S. C. Takeshita, D.Sc., (Other)
Subjects: Behavioral Psychology; Behavioral Sciences; Cellular Biology; Neurosciences