Evidence for activation of histamine H3 autoreceptors during handling stress in the prefrontal cortex of the rat

On-line microdialysis of histamine in 10-min samples of the prefrontal cortex of the conscious rat is described. The HPLC-fluorescent assay for histamine in dialysates has been significantly simplified by using only one postcolumn reagent line instead of the three reagent lines described in earlier methods. The method is selective, sensitive (detection limit: 2-3 fmol on column), and linear over a large concentration range. Basal values of histamine decreased to about 50% of basal levels during infusion of tetrodotoxin (5 x 10(-6) M). Handling rats for 15 min increased histamine in dialysates to about 300% of basal levels. When tetrodotoxin (10(-6) M) was applied during handling the increase in histamine release was strongly (about 80%) suppressed. The handling-induced increase in histamine was used as a paradigm to investigate the functional activity of histamine H3 autoreceptors during mild stress or arousal. An H3 receptor specific agonist (alpha-methylhistamine; 10(-5) M) and antagonist (thioperamide; 10(-5) M) were infused into the frontal cortex via the microdialysis probe. The effect of handling on histamine release was potentiated during infusion of thioperamide and fully suppressed during infusion of alpha-methylhistamine. These results clearly illustrate the efficacy of the H3 autoreceptor in modulating stimulated histamine release during natural stimulatory conditions.