Journal of Neuroimmune Pharmacology

, Volume 7, Issue 3, pp 599–608 | Cite as

D1/NMDA Receptors and Concurrent Methamphetamine+HIV-1 Tat Neurotoxicity

ORIGINAL ARTICLE
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Accepted:

Abstract

The interactive effects of HIV-1 infection and methamphetamine (METH) abuse in producing cognitive dysfunction represent a serious medical problem; however, the neural mechanisms underlying this interactive neurotoxicity remain elusive. In this study, we report that a combination of low, sub-toxic doses of METH + HIV-1 Tat 1–86 B, but not METH + HIV-1 gp120, directly induces death of rodent midbrain neurons in vitro. The effects of D1- and NMDA-receptor specific antagonists (SCH23390 and MK-801, respectively) on the neurotoxicity of different doses of METH or HIV-1 Tat alone and on the METH + HIV-1Tat interaction in midbrain neuronal cultures suggest that the induction of the cell death cascade by METH and Tat requires both dopaminergic (D1) and N-methyl D-aspartate (NMDA) receptor-mediated signaling. This interactive METH+Tat neurotoxicity does not occur in cultures of hippocampal neurons, which are predominately glutamatergic, express very low levels of dopamine receptors, and have no functional dopamine transporter (DAT). Thus, the presence of a subpopulation of neurons capable of dopamine release/uptake is essential for METH+Tat induction of the cell death cascade. Overall, our results support the hypothesis that METH and HIV-1 Tat disrupt the normal conjunction of signaling between D1 and NMDA receptors, resulting in neural dysfunction and death.

Keywords

Cell culture HIV-1 Tat HIV-1 gp120 SCH23390 MK-801 
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Notes

Acknowledgements

This work was supported by NIH grants DA031604, DA011337, DA013137, HD043680.

Conflict of interest

The authors declare no conflict of interest.

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of PsychologyUniversity of South CarolinaColumbiaUSA

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