Effects of the Histamine H₃‐Agonist (R)‐α‐Methylhistamine and the Antagonist Thioperamide on Histamine Metabolism in the Mouse and Rat Brain

Abstract: To study the feedback control by histamine (HA) H³‐receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H₃‐agonist, (R)‐α‐methylhistamine, and an H₃‐antagonist, thioperamide, on the pargyline‐induced accumulation of tele‐methylhistamine (t‐MH) in the brain of mice and rats were examined in vivo. (R)‐α‐Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady‐state t‐MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)‐α‐methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline‐induced increase in the t‐MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline‐induced t‐MH accumulation by ∼70% 1 and 2 h after treatment. Lower doses of (R)‐α‐methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline‐induced t‐MH accumulation in the mouse brain. In the rat, (R)‐α‐methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline‐induced t‐MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.