Regulation of Astrocyte Mitochondrial Function and Oxidative Stress by Trace Amine Associated Receptor 1 in the context of Methamphetamine Abuse and HIV-Associated Neurocognitive Disorders.




Cisneros, Irma
Borgmann, Kathleen
Ghorpade, Anuja PhD


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As a psychostimulant, methamphetamine (METH) use leads to long-lasting, euphoric effects. Between 10- 15% of human immunodeficiency virus-1 (HIV-1) patients report METH abuse, which exacerbates HIV-1 infection, accelerating the onset of HIV-associated neurocognitive disorders (HAND) and immune dysfunction. Neuroinflammation, glial activation, oxidative stress and excitotoxicity contribute to METH and HIV neuropathogenesis. However, the mechanisms through which METH and HIV affect astrocyte function are unclear. Recently, we reported trace amine associated receptor 1 (TAAR1) as a novel astrocyte receptor for METH. Previous studies suggest TAAR1 activity may be regulated by G-protein promiscuity and desensitization by b-arrestin. We hypothesize that HIV-relevant stimuli upregulate astrocyte-TAAR1 expression and that METH exposure induces alterations in TAAR1 activation and intracellular localization, thus contributing to astrocyte dysfunction. To examine TAAR1 expression was assessed by real-time PCR and fluorescent microscopy in human astrocytes in the context of HIV and METH exposure. Changes in EAAT2, which could impair astrocyte ability to clear glutamate, were examined in parallel. To assess TAAR1 regulation by interacting partners, b-arrestin phosphorylation and co-immunoprecipitation studies were performed. Further, downstream outcomes of TAAR1-mediated cAMP and calcium signaling were evaluated, focusing on mitochondrial function and oxidative stress. TAAR1 expression is increased by HIV-relevant stimuli; while EAAT2 expression is concurrently decreased. TAAR1 localizes throughout the cell body in non-activated astrocytes and becomes perinuclear, increasing in the ER during gliosis. b-arrestin is activated by IL-1b and associates with astrocyte-TAAR1. Mitochondrial dysfunction increases with METH and HAND-relevant activation, leading to reactive oxygen species. These studies delineate how dysregulation of TAAR1 may contribute to astrocyte-mediated neurodegeneration during HAND and METH abuse, while also revealing a novel therapeutic target in astroglia.