Project 4

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Though much research has been devoted to the characterization of METH- and HIV-1 viral-induced toxicity; very little is known about the neurophysiological effects of acute and chronic METH on the functional integrity of the CNS and the combined effects of HIV-1 like infection with METH neuropharmacology. Elucidating the cellular mechanisms responsible for these interactions is essential for understanding the sequence of neurophysiological events leading to METH and HIV-1- induced neurotoxicity and thus,, determining in a rational manner, the potential role of METH in HIV-1 viral infection. The objectives of our component are to determine: (a) whether the effects of METH on the murine hippocampus are a function of the treatment schedule and the time following the last drug administration; (b) whether METH produces additive or synergistic effects accelerating the progression of the functional deficits of NeuroAIDS; and (c) whether selected CNS pro- inflammatory cytokines (IL6, INFalpha) or the HIV-1 coat protein gp120 are essential elements in the synergy between METH neurotoxicity and NeuroAIDS pathogenesis. We will study hippocampal (CA1 and dentate gyrus) neurons using extracellular and intracellular techniques in both in vivo and in vitro preparations. We will determine their neuronal excitability, membrane, membrane and synaptic properties and in vitro preparations. We will determine their neuronal excitability, membrane and synaptic properties, local circuit interactions and synaptic plasticity. In addition, we will characterize hippocampal synaptic plasticity and the neuronal modulatory effects of afferent inputs from subcortical structures on hippocampal dentate function in vivo. These data will help determine whether basic properties of the METH treatment such as the dose of METH, the history of METH treatment, the treatment threshold for seizure activity, and on hippocampal physiology. The studies will also identify the interactions between METH and of specific isolation of specific neuronal populations and neurotransmitter systems prone to be targets of NeuroAIDS and METH neuropharmacology. By characterizing the effects of METH treatment and HIV-1-like infection on hippocampal function, these studies will contribute important information about the combined effects of HIV-1 like infection and METH neuropharmacology and will provide critical data for the future identification of beneficial approaches for the treatment and prevention of these conditions.