title: Cocaine-mediated enhancement of Tat toxicity in rat hippocampal cell cultures: the role of oxidative stress and D1 dopamine receptor.
abstract: It is becoming widely accepted that psychoactive drugs can significantly alter the progression of neuropathological changes in the HIV-infected brain. The use of cocaine can aggravate the neurotoxic effects of HIV-1 proteins such as HIV-1 transactivating protein Tat and virus' envelope protein gp120. HIV-1 Tat is believed to play an important role in pathogenesis of HIV dementia (HAD). Tat is neurotoxic and a constantly growing body of evidence suggests that the toxic effects of Tat are oxidative stress-dependent. The current study reports that recombinant Tat 1-72 triggered mitochondrial depolarization, increased intracellular production of reactive oxygen species (ROS) and protein oxidation, and caused neuronal degeneration in primary hippocampal rat cell cultures. A 10 microM dose of the antioxidant Trolox, the water-soluble analog of Vitamin E, ameliorated increased intracellular ROS production and prevented cell viability decline in Tat-treated cell cultures. This fact demonstrates that Tat-induced changes in neuronal oxidative status play an important role in the mechanism of Tat neurotoxicity. While non-toxic by itself, a physiologically relevant dose of cocaine (1.5 microM) significantly enhanced Tat-induced oxidative stress and neurotoxicity in rat hippocampal cell cultures. The antioxidant Trolox significantly improved the survival of neurons exposed to the combination of 50 nM Tat and 1.5 microM cocaine but did not provide complete protection. The specific D1 dopamine receptor antagonist SCH 23390 (10 microM) did not affect Tat toxicity, but did suppress cocaine-mediated potentiation of Tat toxicity. Our results demonstrate that cocaine-mediated potentiation of Tat neurotoxicity may be related to its ability to augment Tat-induced oxidative stress.
authors.affiliation: Department of Psychology, Program in Behavioral Neuroscience, University of South Carolina, Columbia, SC 29208, USA. aksensov@gwm.sc.edu
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Aksenov
authors.forename: Marina V
authors.initials: MV
authors.lastname: Aksenova
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.forename: Philip D
authors.initials: PD
authors.lastname: Ray
authors.forename: Charles F
authors.initials: CF
authors.lastname: Mactutus
authors.forename: Rosemarie M
authors.initials: RM
authors.lastname: Booze
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003042:Cocaine / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D005260:Female; D015696:Gene Products, tat / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008566:Membranes / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D002839:Chromans; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D015696:Gene Products, tat; D017382:Reactive Oxygen Species; D017447:Receptors, Dopamine D1; D014810:Vitamin E; D003042:Cocaine; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid