Cocaine-mediated enhancement of Tat toxicity in rat hippocampal cell cultures: The role of oxidative stress and D1 dopamine receptor

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-I 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 mu M 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 mu M) 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 mu M cocaine but did not provide complete protection. The specific D I dopamine receptor antagonist SCH 23390 (10 mu M) 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. (c) 2005 Elsevier Inc. All rights reserved.