| Human Immunodeficiency Virus-1 (HIV-1) infection is frequently accompanied by nervous system complications, and in 20-30% of the infected individuals, results in a chronic neurodegenerative disorder called HIV-1 associated dementia (HAD). Dysfunction of the dopaminergic system is a feature of HAD. As a result, a significant proportion of the affected population exhibit motor abnormalities. Of particular concern is the finding that HIV-1 infected patients who also abuse the street drug methamphetamine (MA) exhibit more severe encephalitis and neuronal damage compared to HIV-1 positive patients without a history of drug abuse. Prior studies indicated that combined exposure to HIV-1 protein Tat and MA resulted in enhanced neurotoxicity to the dopaminergic system. The objective of this dissertation was to understand the underlying mechanisms of this enhanced dopaminergic neurotoxicity. Neurochemical and neuroanatomical studies carried out in Sprague-Dawley rats indicated an extensive degeneration and loss of dopaminergic terminals with sparing of the substantia nigra in those rats exposed to both Tat and MA. These events were preceded by an increase in oxidative stress in the striatum. Significant activation of astrocytes and microglia was observed in animals exposed to Tat or Tat+MA, but the findings did not support the premise that enhanced neurotoxicity seen with Tat+MA was a consequence of an enhanced glial response to Tat+MA treatment. Analysis of cytokines in the striatum revealed a marked elevation in the chemokine monocyte chemotactic protein-1 (MCP-1) and tissue inhibitor of metal loproteinase-1 (T1MP-1). Further, weak but significant{09}increases were observed with interleukin-1alpha, cytokine{09}induced neutrophil chemoattractant-3, ciliary neurotrophic factor and macrophage inflammatory protein-3alpha. The significance of MCP-1 was tested in mice lacking the gene for MCP-1. In wild-type mice, Tat+MA treatment caused enhanced loss of dopamine; whereas, in MCP-1 knock out mice this interaction between Tat and MA was prevented. In addition, blood brain barrier disruption and monocyte infiltration was noticed in Tat and Tat+MA-treated rats. The findings suggest a possibility that interaction of HIV-1 infection and concurrent drug abuse might profoundly increase infiltration of peripheral monocytes and macrophages with subsequent release of cytotoxic mediators resulting in enhanced neurotoxicity to the dopaminergic system. |
