Several lines of evidence indicate that the basal ganglia are highly susceptible to infection with the human immunodeficiency virus (HIV). However, the pathogenesis of basal ganglia dysfunction is not well understood. Patients with HIV infection often abuse drugs such as methamphetamine, a drug that is well known to also cause long-term structural and functional changes to the basal ganglia. There is now mounting evidence that """"""""virotoxins"""""""" (viral products released from infected cells) and methamphetamine share a common mechanism, which leads to neuronal damage. Two such products are the HIV proteins gp120 and Tat. In this proposal, we will examine the degree of synergy between these virotoxins and methamphetamine by determining the severity of damage they cause to the dopaminergic system in vivo and to human cortical neurons in vitro. To identify common mechanisms that lead to neuronal dysfunction and ultimately, to cell death, we will also examine two pathophysiological processes that contribute independently to virotoxin and MA toxicity, namely reactive oxygen species and the cytokine TNF-alpha. In studying these two processes, we will 2) measure production of compounds of interest (e.g. reactive oxygen species and TNF-alpha) and determine the efficacy of a variety of inhibitors on neurotoxicity. To accomplish these goals, we will assess the effects of intrastriatal injections of virotoxins in animals treated with methamphetamine and in vitro in human cortical neurons where cell types can be manipulated.
