DESCRIPTION: (Applicant's Abstract) Opiate drugs alter the pathogenesis of AIDS. The progression to AIDS dementia in HIV-1-positive individuals may be more rapid in opiate drug abusers than non-abusers. Brain regions with a high number/density of opioid receptors, such as the striaturn and hippocampus, display increased viral loads and are preferentially susceptible to HIV infection. Although HIV itself propagates in microglia and astroglia, HIV-1 protein "virotoxins," including gp120 and Tat, are subsequently released and cause the degeneration of neighboring neurons and glia. Despite evidence of an enhanced vulnerability of neurons and glia to HIV following opiate exposure, the reasons for the susceptibility are not understood since opioids can be neuroprotective or promote apoptosis. Our laboratory and others discovered that phenotypically distinct subsets of glia express mu opioid receptors, and chronic exposure to opiate drugs of abuse destabilize ion homeostasis and cytokine production in neurons and/or glia. Our preliminary data indicate that opiates exacerbate the toxicity to HIV virotoxin-exposed striatal neurons and destabilize Ca 2+ in astroglia. We predict the preferential susceptibility of HIV-1 afflicted individuals to opiates may result from the selective vulnerability of p opioid receptor-expressing neuronsandglia. Our hypothesis is that opiates will directly modify the toxic effects of HIV-1 proteins in opioid receptor-expressing neurons and astroglia. To test the hypothesis, we will explore the role of mu receptors using pharmacologic and genetic (mu receptor knockout mice) strategies. Aim 1 will assess the effects of opiate drugs on the pathogenesis of HIV-1 virotoxin-exposed (gp l20 or Tat) mu receptor-expressing striatal neurons, astroglia, and microglia. Aim 2 will identify morphine-induced alterations in viability, dendritic pathology, reactive astrogliosis, and microglial infiltration/activation in the striata of mice stereotaxically injected with gp120/Tat viral proteins in vivo. Aim 3 will determine whether mu opiates alter gpl20/Tat-induced destabilization of intracellular Ca 2+ and cytokine production. Our goal is to determine the mechanisms by which opioids contribute to the pathobiology of HIV infection in the central nervous system, and to identify interactive events that could be targeted for therapeutic intervention.