Alcohol dependence or abuse is often observed in some populations of patients infected with human immunodeficiency virus type-1 (HIV-1). However, the consequences of alcohol intake in those who are HIV- 1 infected, with regard to function of the brain, have been little studied. This is significant in that HIV-1 infection often results in motor and cognitive impairments, collectively termed HIV-associated dementia (HAD). Long-term ethanol intake produces increased expression or sensitivity of N-methyl-D-aspartate type glutamate receptors (NMDAr). This effect may sensitize the brain to insult caused by excitotoxins such as the HIV-1 protein Tat, a viral transcription factor thought to contribute to the development of HAD. In vitro and in vivo studies using Tat have shown that it causes NMDAr-mediated excitation, Ca 2+ influx into neurons, and neurotoxicity. Thus, it was hypothesized that chronic ethanol exposure would sensitize the brain to the neurotoxic effects of Tat.
The aims of these studies are to: 1. Determine if chronic ethanol ingestion sensitizes the NMDAr system to the detrimental effects of intra-hippocampal Tat injection on behavior and neuronal viability in rats; 2. Determine if Tat (1-72 and 1-86 amino acid forms) may directly interact with specific sites on the NMDAr using radioligand binding studies of rat hippocampus; 3. Determine the role of NMDAR polyamine-site over-activity and Ca 2v influx into neurons in the ability of chronic ethanol exposure to sensitize the hippocampus to Tat toxicity. These studies will employ fluorescent microscopy and immunohistoehemical methods in an organotypic slice-culture model derived from male rats; and 4. Evaluate the ability of novel, synthetic NMDAr polyamine-site antagonists to attenuate the neurodegenerative and behavioral effects of ethanol and Tat exposure. In sum, these studies are designed to elucidate the means by which ethanol intake sensitizes the brain to Tat toxicity and to identify potential therapeutic strategies that may be useful in reducing the incidence of neurological problems caused by HIV-1 infection in those who abuse alcohol or are alcohol-dependent.
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