TY - JOUR
T1 - Methamphetamine and HIV-1-induced neurotoxicity
T2 - Role of trace amine associated receptor 1 cAMP signaling in astrocytes
AU - Cisneros, Irma E.
AU - Ghorpade, Anuja
N1 - Funding Information:
Research reported in this publication was supported by 5R01DA025566 to AG/YP and by F31DA037832 to IC from the National Institute on Drug Abuse of the National Institutes of Health (NIH). We appreciate the assistance of the Laboratory of Developmental Biology for providing us with human brain tissues; also supported by NIH Award Number 5R24HD000836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. I would like to acknowledge Kathleen Borgmann who assisted with manuscript editing and Lin Tang for cell culture support.
PY - 2014/10
Y1 - 2014/10
N2 - Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10-15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH ± HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.
AB - Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10-15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH ± HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.
KW - Astrocytes
KW - Human immunodeficiency virus-1
KW - Methamphetamine
KW - Trace amine associated receptor 1
KW - cAMP
UR - http://www.scopus.com/inward/record.url?scp=84903826066&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2014.06.011
DO - 10.1016/j.neuropharm.2014.06.011
M3 - Article
C2 - 24950453
AN - SCOPUS:84903826066
SN - 0028-3908
VL - 85
SP - 499
EP - 507
JO - Neuropharmacology
JF - Neuropharmacology
ER -