IMIDAZOLEACETIC ACID, A GAMMA-AMINOBUTYRIC-ACID RECEPTOR AGONIST, CANBE FORMED IN RAT-BRAIN BY OXIDATION OF HISTAMINE

It is generally accepted that in mammalian brain histamine is metaboli zed solely by histamine methyltransferase (HMT), to form tele-methylhi stamine, then oxidized to tele-methylimidazoleacetic acid. However, hi stamine's oxidative metabolite in the periphery, imidazoleacetic acid (IAA), is also present in brain and CSF, and its levels in brain incre ase after inhibition of HMT. To reinvestigate if brain has the capacit y to oxidize histamine and form IAA, conscious rats were injected with [H-3]histamine (10 ng), either into the lateral ventricles or cistern a magna, and decapitated 30 min later. in brains of saline-treated rat s, most radioactivity recovered was due to tele-methylhistamine and te le-methylimidazoleacetic acid. However, significant amounts of tritiat ed IAA and its metabolites, IAA-ribotide and IAA-riboside, were consis tently recovered. In rats pretreated with metoprine, an inhibitor of H MT, labeled IAA and its metabolites usually comprised the majority of histamine's tritiated metabolites. [H-3]Histamine given intracisternal ly produced only trace amounts of oxidative metabolites. Formation of IAA, a potent GABA-A agonist with numerous neurochemical and behaviora l effects, from minute quantities of histamine in brain indicates a ne ed for reevaluation of histamine's metabolic pathway or pathways in br ain and suggests a novel mechanism for interactions between histamine and the GABAergic system.