Possible modulatory effects of histamine (HA) on electrically-evoked neurotransmitter release from slices of a number of rat brain regions were investigated. Neither the release of [(3)H]DA nor that of [(14)C]ACh from neostriatal slices were affected by HA (up to 3 ?M). In contrast, HA (1 ?M) inhibited the release of [(3)H]NA from slices of both frontal cortex and hypothalamus by 25% and 37%, respectively. The strongest inhibitory effects of HA (40-50% at 1 ?M) were found with regard to [(3)H]5-HT release from slices of all three brain regions examined. In the frontal cortex [(3)H]5-HT release was inhibited by HA with an EC(50) of about 0.1 ?M and further pharmacological experiments suggested that the receptors involved in this inhibitory effect are of the H(3) type. Also in view of data reported by others it is suggested tentatively that in general presynaptic modulation of neurotransmitter release by histamine, if it occurs, involves activation of H(3) receptors.