Inhibitors of histamine methylation in brain promote formation of imidazoleacetic acid, which interacts with GABA receptors.
In brain, the precursor of imidazoleacetic acid (IAA), a GABAA agonist but a GABAC antagonist, is not known. In the periphery, IAA derives from oxidation of histamine. But in brain, histamine is thought to be metabolized solely by histamine methyltransferase (HMT), forming tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA). We showed that [3H]-histamine (intracerebroventricularly) could be converted to IAA in brains of rats, a process increased by inhibition of HMT. This demonstrated that brain can oxidize histamine and suggested that endogenous histamine might also be oxidized if HMT activity were reduced. We examined in rat cerebral cortex, effects of the following HMT inhibitors (mg/kg i.p.): metoprine (10), tacrine (10), velnacrine (10, 30), and physostigmine (1,2). Tacrine was a potent inhibitor (Ki approximately 22 nM). To measure histamine in tissue that contained HMT inhibitors, we developed a gas chromatography-mass spectrometry method. After 2 h, all drugs reduced endogenous levels of t-MH and t-MIAA and increased levels of histamine and IAA. Our results show that inhibition of HMT promotes oxidation of histamine in brain, probably by shunting histamine to an alternative metabolic pathway. Formation of IAA provides a novel interaction between histaminergic and GABAergic systems in brain. Accumulation of IAA should be considered when inhibitors of HMT are used to probe brain histamine function.
Prell
G D
GD
Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, New York, USA.
Morrishow
A M
AM
Duoyon
E
E
Lee
W S
WS
D000818:Animals; D001921:Brain / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006632:Histamine / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism*; D008297:Male; D008745:Methylation / Q000187:drug effects; D010830:Physostigmine / Q000494:pharmacology; D011739:Pyrimethamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D013619:Tacrine / Q000031:analogs & derivatives / Q000494:pharmacology
D007093:Imidazoles; D018079:Receptors, GABA; C006308:metoprine; D013619:Tacrine; D006632:Histamine; D010830:Physostigmine; C005954:imidazoleacetic acid; C056424:velnacrine; D011739:Pyrimethamine