Histamine stimulation of phosphoinositide breakdown has been studied in brain cortex from developing rats by measuring the accumulation of [3H]inositol monophosphate in lithium-treated slices prelabeled with [3H]inositol. Histamine stimulated phosphoinositide hydrolysis as early as day 3 after birth. The maximal response increased about 3-fold up to day 15 and remained essentially at the same level until adulthood. This developmental pattern contrasted with the 8-fold increase in [3H]mepyramine binding to histamine H1 receptors which takes place from the first to the end of the fourth week of life. Nonlinear regression analysis of concentration-effect curves for histamine generated at 6, 10, and 15 days of age revealed the presence of two components in the response, whereas a single component was found in adults. A high potency component showed EC50 values increasing from 6.4 microM at day 6 to 26.5 microM at day 15, and its contribution to the maximal response augmented from 65.8% to 78.9% during the same period. In 6-day-old animals, the H1 receptor agonists N alpha-methylhistamine and N alpha,N alpha-dimethylhistamine produced single-component responses with maximal effects similar to that estimated for the high potency component for histamine, and their relative potencies were consistent with an H1 receptor-mediated response. Inhibition constants for mepyramine, calculated from the parallel displacement of the concentration-response curves for N alpha-methylhistamine and the high potency component for histamine (6.3 nM and 10.8 nM, respectively) closely agreed with the reported affinity of rat brain H1 receptors for this compound. The low potency component of the response (EC50 = 175 microM at day 6 and EC50 = 260 microM at day 15) did not involve histamine-H2, serotonin 5-HT2, alpha 1-adrenergic, or muscarinic receptors. Pretreatment of 6-day-old cortical slices with the irreversible antagonist phenoxybenzamine, at concentrations that completely abolish [3H]mepyramine binding, left about 25% of the response to 1 mM histamine unaffected. This portion of the response, which was, moreover, insensitive to 1 microM mepyramine, was of a magnitude similar to that of the low potency component. Thus, at early stages of rat brain development, histamine induces phosphoinositide hydrolysis in part through a mechanism different from activation of H1 receptors. The loss of histamine potency and efficacy at H1 receptors throughout development is discussed and the natural occurrence of H1 receptor subsensitivity suggested.