Astrocytes from a variety of sources, including the human UC-11MG astrocytoma line, express receptors for histamine on their plasma membranes, but the function of these receptors is largely unknown. Here we report studies on the effect of histamine on newly synthesized glycogen in the human astrocytoma-derived cell line, UC-11MG. We have found [3H]glycogen hydrolysis with a EC50 of 2 microM and a maximum effect of 30% at 300 microM histamine. The glycogenolytic effect of histamine was completely blocked by the H1 receptor antagonist, mepyramine, and was insensitive to the H2 receptor antagonist, cimetidine. Histamine-induced glycogenolysis was significantly reduced in the absence of extracellular Ca2+ and the residual response could be accounted for by Ca2+ released from intracellular stores. The Ca2+ ionophore, ionomycin, induced a similar concentration-dependent increase in both intracellular Ca2+ concentration and in glycogenolysis. These results suggest that one function of astrocytic histamine receptors in vivo may be the stimulation of glucose release from astrocytes, and that this process is mediated by increased intracellular free Ca2+. The glycogenolytic effect of histamine and other neurotransmitters in different systems, and the possible implication of astrocytic glycogenolysis in the pathophysiology of ischemia are discussed.