Dithiothreitol (1 mM) caused a 340-fold shift of the concentration-response curve for histamine-induced [3H]inositol monophosphate ([3H]IP1) accumulation in slices of rat cerebral cortex prelabelled with [3H]inositol. Dithiothreitol had no significant effect on carbachol-induced [3H]IP1 accumulation. The effect of dithiothreitol appeared to be at the level of the H1-receptor, since curves of histamine inhibition of [3H]mepyramine binding to a membrane fraction from rat cerebral cortex were shifted to lower concentrations by dithiothreitol, with a similar concentration-dependence for dithiothreitol as observed for potentiation of [3H]IP1 accumulation. The small shift of the curve of histamine inhibition of [3H]mepyramine binding by a stable GTP analogue, 5'-guanylylimidodiphosphate, was not increased in the presence of dithiothreitol. Histamine-induced [3H]IP1 accumulation in human HeLa cells was also potentiated by dithiothreitol, but the decrease in the EC50 was only 3-fold. It is suggested that differences in the magnitude of the effect of dithiothreitol on histamine H1-receptor mediated responses between tissues may reflect in part the position of the concentration-response curve in the absence of dithiothreitol.