Abstract
Our previous studies demonstrated that the psychostimulant methamphetamine (MA) and the human immunodeficiency virus-1 (HIV-1) protein Tat interacted to cause enhanced dopaminergic neurotoxicity. The present study examined whether tumor necrosis factor-alpha (TNF-alpha) mediates the interaction between Tat and MA. In Sprague-Dawley rats, injections of Tat caused a small but significant increase in striatal TNF-alpha level, whereas MA resulted in no change. The increase in TNF-alpha induced by Tat + MA was not significantly different from that induced by Tat alone. Temporal analysis of TNF-alpha levels revealed a 50-fold increase 4 h after Tat administration. In C57BL/6 mice, Tat + MA induced a 50% decline in striatal dopamine levels, which was significantly attenuated in mice lacking both receptors for TNF-alpha. TNF-alpha synthesis inhibitors significantly attenuated Tat + MA neurotoxicity in hippocampal neuronal culture. The results suggest that Tat-induced elevation of TNF-alpha may predispose the dopaminergic terminals to subsequent damage by MA.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AIDS Dementia Complex / immunology
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AIDS Dementia Complex / physiopathology
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AIDS Dementia Complex / virology
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Amphetamine-Related Disorders / immunology
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Amphetamine-Related Disorders / metabolism
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Amphetamine-Related Disorders / physiopathology
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Animals
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Basal Ganglia / drug effects
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Basal Ganglia / immunology
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Basal Ganglia / virology
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Cells, Cultured
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Disease Models, Animal
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Dopamine / metabolism
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Dopamine Uptake Inhibitors / toxicity
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Encephalitis / immunology*
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Encephalitis / physiopathology
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Encephalitis / virology
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Gene Products, tat / immunology
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Gene Products, tat / metabolism
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Gene Products, tat / toxicity*
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Humans
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Male
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Methamphetamine / toxicity*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oxidative Stress / drug effects
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Oxidative Stress / immunology*
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Presynaptic Terminals / drug effects
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Presynaptic Terminals / immunology
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Presynaptic Terminals / virology
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation / drug effects
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Up-Regulation / immunology
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tat Gene Products, Human Immunodeficiency Virus
Substances
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Dopamine Uptake Inhibitors
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Gene Products, tat
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Protein Synthesis Inhibitors
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Tumor Necrosis Factor-alpha
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tat Gene Products, Human Immunodeficiency Virus
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Methamphetamine
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Dopamine