Dopamine Dysregulation and Oxidative Stress in HIV and Methamphetamine Induced Cognitive Impairment - PROJECT SUMMARY Public health in the US is facing two overlapping epidemics, namely, substance use disorder (SUD) and HIV infection. Methamphetamine (METH) use is steadily rising in the U.S., with one study reporting a 43% increase in past-year usage between 2016 and 2019. Clinically, amphetamines, including METH, are associated with cognitive decline and a variety of psychiatric disorders, including depression, psychosis, and anxiety. METH use is a prominent risk factor for HIV infection and correlates with poor adherence to antiretrovirals and, in turn, with worse response to therapy. HIV infection is associated with neurocognitive and neuropsychiatric deficits, loss of dopaminergic neurons, neuroinflammation, and increased neural oxidative stress. The loss of dopaminergic neurons in HIV infection may play a critical role in interactions with METH, as METH’s biological and psychostimulatory effects are primarily mediated through dopamine. Given the public health impact of the METH use and HIV epidemics, there is a critical need to understand the mechanisms driving concomitant HIV and METH-associated neuropsychiatric disorders. The central hypothesis of this proposal is that METH and HIV infection, individually and in combination, contribute to the development of neuropsychiatric disorders in a sex-specific manner. Mechanistically, we propose that an increase in dopamine-induced neuroexcitation, oxidative stress, and mitochondrial damage are responsible for these effects. To address this hypothesis, we will administer quetiapine to mice infected with ecoHIV, a murine tropic HIV, and/or receiving METH. Quetiapine is an atypical antipsychotic that blocks dopamine D1 and D2 receptors while agonizing serotonin receptors. We will evaluate the effect of quetiapine on the neurocognitive deficits and depressive symptoms (Aim 1), and pro-inflammatory and oxidative changes (Aim 2) observed in my preliminary studies on mice receiving METH and/ or infected with HIV. We anticipate that quetiapine will block the excitotoxic effects of dopaminergic neurons and reduce inflammation and oxidative stress, ameliorating the neurocognitive symptoms induced by HIV and /or METH. Additionally, we anticipate improvement of depressive symptoms through both the reduction of neuroinflammation and quetiapine-induced serotonin agonism. My overarching goal is to address a gap of knowledge in the mechanism of HIV and METH induced neuropsychiatric disorders and neurotoxicity by providing proof of concept that quetiapine, an FDA-approved antipsychotic, can prevent or ameliorate HIV and METH induced neurotoxicity and neuropsychiatric disorders. The data generated from Aims 1 and 2 would provide new insights into the treatment of HIV- and METH-induced neuropsychiatric disorders while also playing a crucial role in my development as a physician-scientist with hopes of working in SUD and infectious diseases.
