TRANSIENT METHAMPHETAMINE-ASSOCIATED HYPERTHERMIA MODULATES ASTROCYTE TRACE AMINE ASSOCIATED RECEPTOR-1 ACTIVATION AND EXACERBATES HIV-1-INDUCED NEURODEGENERATION

Purpose: Methamphetamine (METH) is a highly abused and addictive psychostimulant. METH heightens sexual arousal and decreases inhibition increasing the probability for acquiring human immunodeficiency virus-1 (HIV-1). HIV-1 results in cognitive effects, such as HIV-associated dementia (HAD) characterized by similar neurotoxic mechanisms as METH. Astrogliosis and hyperthermia are key pathological features of METH exposure and HAD. In context of our studies, METH abuse increases brain temperature by approximately 2° C, mimicking a fever common during early HIV-1 infection. A moderate increase in brain temperature exacerbates neuroinflammatory processes synergistically effecting METH/HIV-1-associated neurodegeneration. Methods: Astrocytes sensitivity to METH led to the investigation of astrocyte TAAR1 as a receptor mechanism for METH-induced effects in astrocytes. Previously we showed localization and function of astrocyte TAAR1. Documented TAAR1 thermoregulatory responses led the expansion of our studies to investigate METH-associated hyperthermia in METH/HIV-1-induced astrocyte activation. Results: Furthermore, preliminary data suggest TAAR1 regulation in the presence of thermal stress. Elevated temperatures increased GFAP expression and cytokine secretion. We propose activation of astrocyte TAAR1 mediates METH/HIV-1-induced neurodegeneration, further modulated by METH-associated hyperthermia. Conclusions: The results will lead to understanding of the mechanisms and pathological features associated with METH and HIV-1 neurodegeneration and potential therapeutic targets in the CNS.