The postnatal ontogenetic development of the histamine receptor subtypes was studied in rat brain by quantitative receptor autoradiography with highly sensitive imaging plates. H1 receptor binding sites labeled with [3H]pyrilamine were detected on postnatal day 2 (P2) and increased very slowly until P9, and then rapidly reaching the adult levels in the hypothalamus, hippocampus, and amygdala by P16. The densities of H1 receptor binding sites in the cortex, striatum, thalamus, and substantia nigra were relatively low during development. H3 receptor binding sites labeled with [3H](R) alpha-methylhistamine were not detectable until P9. On P9, their density was higher in the substantia nigra than in other regions. Subsequently, H3 receptor binding increased, reaching the adult levels in the substantia nigra on P16 and in the other regions on P23. The histamine concentration was initially very high, but decreased to the adult level by P16. On the contrary, the activity of L-histidine decarboxylase of whole brain tissue was low on P5, and increased markedly from P16 to P23, to the adult level on P30. Administration of (S) alpha-fluoromethylhistidine (FMH), a specific inhibitor of L-histidine decarboxylase (HDC), significantly decreased both the HDC activity and histamine concentration during postnatal development. FMH treatment did not change H1 receptor binding in any brain region, but significantly increased H3 receptors in the substantia nigra and striatum on P23. Unilateral injection of 6-hydroxydopamine into the striatum on P2 resulted in up-regulation of H3 receptor binding sites in the dorsomedial (11%) and dorsolateral (18%) regions of the striatum and substantia nigra (31%) on P23, but no change in the H3 receptor density in the nucleus accumbens or frontal cortex on P11 and P23. These results demonstrate that the developmental patterns of H1 and H3 receptors are heterogeneous and independent of each other. There are marked mismatches of presynaptic and postsynaptic markers of the histaminergic neuron system as in other aminergic systems.