title: D1/NMDA receptors and concurrent methamphetamine+ HIV-1 Tat neurotoxicity.
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.
authors.affiliation: Department of Psychology, University of South Carolina, 1512 Pendleton Street, Barnwell College Building, Columbia, SC 29208, USA. aksenov@mailbox.sc.edu
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Aksenov
authors.forename: M V
authors.initials: MV
authors.lastname: Aksenova
authors.forename: C F
authors.initials: CF
authors.lastname: Mactutus
authors.forename: Rosemarie M
authors.initials: RM
authors.lastname: Booze
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D015497:HIV-1; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000633:toxicity*
chemical_list: D015699:HIV Envelope Protein gp120; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C514793:gp120 protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus; D008694:Methamphetamine