Date of Award
Ph.D. in Pharmaceutical Sciences
Pharmaceutics and Drug Delivery
Dr. Jason Paris
Dr. Kristine Willett
Dr. Nicole Ashpole
The overarching goal of this dissertation was to assess the interaction of HIV-1 Tat protein with opioids like oxycodone and the hypothalamic-pituitary-adrenal (HPA) axis and develop novel therapeutic strategy to restore HPA dysfunction in adult HIV-1 Tat transgenic mice. In the past 3 decades, combined antiretroviral therapeutics (cART) has increased the life expectancy of HIV infected individuals, with a significant decline in the number of deaths. However, due the inability of cART to sufficiently target latent CNS viral reservoirs (predominantly microglia and astrocytes to a lesser extent), approximately 50% of the HIV+ infected population contends with neurological, neuropsychiatric and neuroendocrine complications, but the mechanisms are unknown. The central hypothesis of my dissertation is that neurosteroids like allopregnanolone can restore HIV-1 Tat mediated HPA axis dysregulation and underlying neurological and psychiatric complications, which are exacerbated by clinically prescribed opioids. Chapter 1 demonstrates the ability of HIV-1 Tat to promote HPA dysfunction by elevating basal circulating corticosterone and paradoxical adrenal insufficiency in response to a natural stressor in transgenic Tat-expressing mice, recapitulating the clinical endophenotype. Blocking receptor targets namely corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) in males partially-reinstated the HPA response in Tat-expressing mice implicating GR in these effects. Chapter 2 revealed HIV-1 Tat expression produced neuroHIV symptomatology like anxiety, depression, behavior disinhibition, cognitive impairment and potentiated oxycodone psychomotor effects in various behavioral tasks in adult transgenic mice. Pharmacological blockade of corticotropin-releasing factor receptor (CRF-R) and/or GR via systemic administration of antalarmin and RU-486 attenuated psychomotor and anxiety-like behavior. Moreover, gonadal steroids like estradiol and progesterone ameliorated Tat-mediated neurotoxicity in cell cultures. Chapter 3 demonstrated the neuroprotective capacity of neurosteroids like allopregnanolone and 18 kDa translocator protein (TSPO) ligands to restore HPA dysfunction and concomitantly Tat-mediated behavioral deficits. Given the inability of cART to target Tat, novel adjunctive compounds such as allopregnanolone or TSPO ligands may provide further therapeutic recourse to curtail HIV-1 mediated HPA dysfunction and underlying neurological complications.
Mohammed, Salahuddin, "HIV-1 Tat and Opioids: Implications for Stress-related Psychopathology" (2022). Electronic Theses and Dissertations. 2257.
Available for download on Thursday, August 15, 2024