The pathogenesis of the human immunodeficiency virus (HIV)-associated cognitive/motor complex, or acquired immunodeficiency syndrome (AIDS) dementia complex, is unknown, but it afflicts over 50% of all patients infected with HIV-1. Because neurons are not directly infected with HIV-1, the causes of neuronal dysfunction are undoubtedly indirect. We investigated the role of the astrocyte in the development of AIDS dementia complex, focusing on cytokine and HIV-1 gp120 stimulation of Na+/H+ exchange (NHE) activity of primary rat astrocytes. Our results show that the cytokines tumor necrosis factor-α, interferon (IFN)-γ, and interleukin (IL)-1β (all found to be elevated in the central nervous system of AIDS patients), can stimulate Na+/H+ exchange, but that transforming growth factor-β, IL-2, and IL-6 do not. IFN-γ and gp120-induced activation of Na+/H+ exchange appears to be mediated through activation of tyrosine kinase (TK), because TK inhibitors block the action of IFN-γ and gp120. Additionally, gp120 induces tyrosine phosphorylation of two proteins (~90 and 130 kDa), which is also inhibited by TK inhibitors. The predominant NHE isoform present in rat astrocytes is NHE-1: however, other isoforms are also present. We conclude that Na+/H+ exchange of rat astrocytes can be differentially stimulated by cytokines and HIV-1 gp120. We hypothesize that the resultant increase in intracellular pH with its concomitant changes in astrocyte membrane permeability properties produces an imbalance in the K+ and glutamate microenvironment of the neurons, leading to a rise in intraneuronal Ca2+ and eventual neuronal dysfunction and/or demise.