Cytokine levels are elevated in the central nervous system (CNS) in a variety of disorders and may contribute to abnormalities in CNS function associated with the disorders. To begin to understand the mechanisms through which elevated cytokines affect CNS cells, we have examined the effects of cytokines on astrocyte physiology within minutes of application as well as 24 h later. Both standard cultured cortical astrocytes and those induced to further differentiate by pre-treatment with forskolin were examined. Such treated astrocytes may more closely resemble those in brains exhibiting elevated cytokine levels. The cytokine focused upon was interleukin-1-beta (II-1 beta). Gamma-interferon (gamma-IFN) and tumor necrosis factor-alpha (TNF-alpha) were also examined in some studies. Changes in calcium levels produced by acute application of these cytokines were measured. The most pronounced effect was an immediate calcium elevation in response to II-1 beta in the forskolin pre-treated astrocytes. Longer term treatment with IL-1 beta in forskolin pre-treated astrocytes enhanced the calcium response to quisqualate stimulation, a glutamate neurotransmitter receptor agonist. These results suggest that situations that cause chronic changes in cytokine levels and involve astrocytic differentiation, such as chronic CNS infection or Alzheimer's disease, could change astrocytic responses to normal stimuli. Such changes may result in altered astrocytic support of neurons and therefore cause changes in CNS function.