LACK OF A PRECURSOR-PRODUCT RELATIONSHIP BETWEEN HISTAMINE AND ITS METABOLITES IN BRAIN AFTER HISTIDINE LOADING

Levels of histamine and its major metabolites in brain, tele-methylhis tamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), were measu red in rat brains up to 12 h after intraperitoneal administration of L -histidine (His), the precursor of histamine. Compared with saline-tre ated controls, mean levels of histamine were elevated at 1 h (+102%) a fter a 500 mg/kg dose; levels of t-MH did not increase. following a 1, 000 mg/kg dose, mean histamine levels were increased for up to 7 h, pe aked at 3 h, and returned to control levels within 12 h. In contrast, levels of t-MH showed a small increase only after 3 h; levels of t-MIA A remained unchanged after either dose. Failure of most newly formed h istamine to undergo methylation, its major route of metabolism in brai n, suggested that histamine was metabolized by another mechanism possi bly following nonspecific decarboxylation. To rest this hypothesis, ot her rats were injected with alpha-fluoromethylhistidine (alpha-FMHis; 75 mg/kg, i.p.), an irreversible inhibitor of specific histidine decar boxylase. Six hours after rats received alpha-FMHis, the mean brain hi stamine level was reduced 30% compared with saline-treated controls. R ats given His (1,000 mg/kg) 3 h after alpha-FMHis (75 mg/kg) and exami ned 3 h later had a higher(+112%) mean level of histamine than rats gi ven alpha-FMHis, followed by saline. Levels of t-MH and t-MIAA did not increase. These results imply that high doses of His distort the simp le precursor-product relationship between histamine and its methylated metabolites in brain. The possibility that some His may undergo nonsp ecific decarboxylation in brain after His loading is discussed. These findings, and other actions of His independent of histamine, raise que stions about the validity of using His loading as a specific probe of brain histaminergic function.