Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function.
The human immunodeficiency virus (HIV)-1 transactivating protein Tat may be pathogenically relevant in HIV-1-induced neuronal injury. The abuse of methamphetamine (MA), which is associated with behaviors that may transmit HIV-1, may damage dopaminergic afferents to the striatum. Since Tat and MA share common mechanisms of injury, we examined whether co-exposure to these toxins would lead to enhanced dopaminergic toxicity. Animals were treated with either saline, a threshold dose of MA, a threshold concentration of Tat injected directly into the striatum, or striatal injections of Tat followed by exposure to MA. Threshold was defined as the highest concentration of toxin that would not result in a significant loss of striatal dopamine levels. One week later, MA-treated animals demonstrated a 7% decline in striatal dopamine levels while Tat-treated animals showed an 8% reduction. Exposure to both MA + Tat caused an almost 65% reduction in striatal dopamine. This same treatment caused a 56% reduction in the binding capacity to the dopamine transporter. Using human fetal neurons, enhanced toxicity was also observed when cells were exposed to both Tat and MA. Mitochondrial membrane potential was disrupted and could be prevented by treatment with antioxidants. This study demonstrates that the HIV-1 'virotoxin' Tat enhances MA-induced striatal damage and suggests that HIV-1-infected individuals who abuse MA may be at increased risk of basal ganglia dysfunction.
Maragos
William F
WF
Department of Neurology, University of Kentucky, Lexington, Kentucky 40536, USA. maragos@pop.uky.edu
Young
Kristie L
KL
Turchan
Jadwiga T
JT
Guseva
Masha
M
Pauly
James R
JR
Nath
Avi
A
Cass
Wayne A
WA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001667:Binding, Competitive / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D004357:Drug Synergism; D015696:Gene Products, tat / Q000633:toxicity*; D015497:HIV-1; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins; D008564:Membrane Potentials / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D000975:Antioxidants; D050483:Dopamine Plasma Membrane Transport Proteins; D015696:Gene Products, tat; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D015102:3,4-Dihydroxyphenylacetic Acid; C079213:RTI 121; D012701:Serotonin; D008694:Methamphetamine; D006897:Hydroxyindoleacetic Acid; D003042:Cocaine; D004298:Dopamine; D006719:Homovanillic Acid