Date of Award
8-16-2024
Document Type
Open Access Dissertation
Department
College of Pharmacy
First Advisor
Jun Zhu
Abstract
Prevalence of HIV-1 Associated Cognitive Disorders (HAND) persists in the era of combined antiretroviral therapies, causing impaired memory, motor function, and decreased quality of life. Evidence from clinical samples of persons with HAND has implicated dopamine, as well as the HIV-1 viral protein transactivator of transcription (Tat) as key molecules associated with disease progression. Through molecular modeling, in vitro and in vivo mutagenesis our lab has characterized Tat as a negative allosteric modulator for monoamine transporters, including the dopamine transporter (DAT), vesicular monoamine transporter (VMAT-2), and norepinephrine transporter. While this work has shed light on how Tat impacts the function of monoamine transporters in isolation, it is not known how Tat’s impact on these monoamine transporters influences overall extracellular DA signaling dynamics. Based on the in vitro and in vivo evidence that Tat inhibits the uptake dopamine through DAT and VMAT-2, we hypothesize that Tat disturbs dopamine homeostasis during neurotransmission events. To investigate this hypothesis, fast scan cyclic voltammetry (FSCV) was used to probe local dynamic changes in DA release in uptake in the striatum of mice expressing Tat. The first study found that Tat expression increased baseline DA release specifically in the dorsomedial striatum, which could be attenuated by the novel DAT allosteric modulator SRI-32743. To further investigate how monoamine transporters contribute to Tat’s effects on DA dynamics, Tat’s effect on response to VMAT-2 inhibitors was profiled. Here, we found that Tat reduced the affinity for the VMAT-2 inhibitor GZ-793A specifically in the nucleus accumbens core using FSCV. Lastly, comorbid methamphetamine (meth) use is highly prevalent among HIV-1 infected persons. As seen with Tat, meth dysregulates DA dynamics by reducing VMAT-2 activity. Therefore, the final aim of this study used FSCV to determine how the combination of Tat expression and meth administration impacted response to GZ-793A. Here we found that together, Tat and meth synergistically down-regulate VMAT-2 activity in the nucleus accumbens core of inducible transgenic mice expressing Tat. These findings shed light on the subregion specific effects of Tat on extracellular dynamics, and how monoamine transporters contribute to Tat’s overall effects on DA neurotransmission. Further, this dissertation highlights novel small molecules which can attenuate Tat’s effects at monoamine transporters as a therapeutic strategy for preventing Tat-induced deficits in dopaminergic function in persons with HAND.
Rights
© 2024, Sarah Davis
Recommended Citation
Davis, S.(2024). Dysregulation of Dopamine Dynamics Through Monoamine Transporters by the HIV-1 Protein Transactivator of Transcription. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/7695