DISPOSITION OF HISTAMINE, ITS METABOLITES, AND PROS-METHYLIMIDAZOLEACETIC ACID IN BRAIN-REGIONS OF RATS CHRONICALLY INFUSED WITH ALPHA-FLUOROMETHYLHISTIDINE
Gd. Prell et al., DISPOSITION OF HISTAMINE, ITS METABOLITES, AND PROS-METHYLIMIDAZOLEACETIC ACID IN BRAIN-REGIONS OF RATS CHRONICALLY INFUSED WITH ALPHA-FLUOROMETHYLHISTIDINE, Journal of neurochemistry, 66(5), 1996, pp. 2153-2159
In mammalian brain, histamine is known to be metabolized solely by his
tamine methyltransferase (HMT), forming tele-methylhistamine (t-MH), t
hen tele-methylimidazoleacetic acid (t-MIAA). We previously showed tha
t imidazoleacetic acid (IAA), a GABA agonist, and histamine's metaboli
te in the periphery, is present in brain where its concentration incre
ased after inhibition of HMT. Also, when [H-3]histamine was given intr
acerebroventricularly to rats, a portion was converted to IAA, a proce
ss increased by inhibition of HMT. These results indicated that brain
has the capacity to oxidize histamine but did not show whether this pa
thway is operative under physiological conditions. To address this que
stion, rats were infused for >4 weeks with alpha-fluoromethylhistidine
(alpha-FMHis), an irreversible inhibitor of histamine's synthetic enz
yme,L-histidine decarboxylase. Compared with controls (untreated and s
aline-treated rats), brain levels of histamine, t-MH, and t-MIAA in al
l regions were markedly reduced in treated rats. As a percentage of co
ntrols, depletion of t-MIAA > t-MH > histamine in all regions, and reg
ional depletions of histamine corresponded to its turnover rates in re
gions of rat brain. In contrast, levels of IAA were unchanged as were
levels of pros-methylimidazoleacetic acid, an isomer of t-MIAA unrelat
ed to histamine metabolism. Results suggest that in brains of rats, un
like in the periphery, most IAA may not normally derive from histamine
. Because histamine in brain can be converted to IAA under certain con
ditions, direct oxidation of histamine may be a conditional phenomenon
. Our results also support the existence of a very slow turnover pool
of brain histamine and use of chronic alpha-FMHis infusion as a model
to probe the histaminergic system in brain.