DESCRIPTION (provided by applicant): The goal of this proposal is to investigate METH-mediated activation of trace amine associated receptor 1 (TAAR1) and the downstream effects that lead to exacerbation of HIV-1 associated neurocognitive disorders in the context of METH-associated transient hyperthermia. As a psychostimulant, methamphetamine (METH) use results in strong, long lasting euphoric effects 1. During which, METH heightens the libido, impairs judgment and leads to risky sexual behavior ultimately increasing the risk of acquiring human immunodeficiency virus (HIV-1) 1, 2. The most severe form, HIV-associated dementia (HAD)3, is mediated by neurotoxic mechanisms including inflammation, glial activation, excitotoxicity, oxidative stress, and hyperthermia 1, 4-6. METH-induced hyperthermia peaks between 102-1030F/390C and brain temperature fluctuations between 10- 40C may contribute to neurodegenerative mechanisms 7, 8. In clinical studies METH dependence has an additive effect on HIV-1 associated neuropsychological deficits by exacerbating these common neuroinflammatory processes 1, 9. We show that astrocytes are sensitive to METH and postulate that trace amine associated receptor 1 (TAAR1) mediates METH-induced effects in astrocytes. As a G-protein coupled receptor activated by trace amines, TAAR1 initiates intracellular cyclic adenosine monophosphate (cAMP) signaling cascades leading to regulation of gene expression and cellular responses. TAAR1 was previously identified as an important neuronal receptor for METH action in dopamine transporter (DAT) regulation, glutaminergic signaling and thermoregulation 10-12. We propose that METH activates astrocyte TAAR1 leading to intracellular cAMP signaling further exacerbating astrocyte-mediated neurotoxicity in the context of HAND and METH- associated transient hyperthermia. We will address this hypothesis through the following aims: AIM 1 To investigate astrocyte TAAR1 regulation in response to METH/HIV-1ADA treatment and associated hyperthermia and AIM 2 To elucidate downstream signaling pathways of METH-induced astrocyte TAAR1 activation and associated transient hyperthermia thereby exacerbating HAND pathology. Completion of these studies will shed light on TAAR1 specific cAMP signaling in astrocytes during HIV-mediated neurodegeneration and METH-associated transient hyperthermia.

PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) abuse has prevailed as a drug epidemic within the United States and worldwide with an estimated 27.4 million users ranging from as young as 12 years of age to older adults. METH abuse increases a users chance of contracting human immunodeficiency virus (HIV). HIV-1-associated dementia (HAD), the most severe manifestation of HIV-1-associated neurocognitive disorders, is an important neurological complication of HIV-1 infection and is characterized by cognitive, behavioral and motor dysfunction. Clinical studies indicate that METH accelerates the onset and severity of the neuroinflammatory processes of HIV-1 infection in the central nervous system (CNS). Our studies will provide a better understanding of the specific mechanistic contributions of activated astrocytes to HIV-1-neuropathogensis during METH abuse.