Biochemical studies on histaminergic systems in mammalian brains.

The effects of (+/-) alpha-fluoromethylhistidine (alpha-FMH), a new histidine decarboxylase (HD) inhibitor, were investigated in vitro and in vivo. Following a preincubation with (+/-) alpha-FMH, brain HD-activity was progressively inhibited and could not be restored by dialysis, thus indicating the irreversible nature of this inhibition. Moreover, in vivo, a single intraperitoneal dose of 20 mg/kg of (+/-) alpha-FMH induced a complete and rapid loss of HD activity in gastric and brain tissues. The time-course of recovery was different according to the tissue studied. At a dose of 100 mg/kg (+/-) alpha-FMH did not modify histamine-N-methyl transferase (HMT), DOPA decarboxylase and glutamate decarboxylase activities. A high affinity binding of 3H-histamine was seen in particulate fractions from rat brains. The regional and subcellular distributions of these binding sites indicate that they are not related to HMT. They are likely to represent post-synaptic HA-receptors in view of their decrease after kainate-induced degeneration of neuronal perikarya in the striatum and their increase following interruption of the histaminergic inputs which suggested a denervation hypersensitivity. However, their pharmacological specificity was distinct from either H1- or H2-receptors and the possibility of a modified conformational state of HA-receptors was raised by the selective effect of guanylnucleotides.