journal of Neurochemistry Lippincott—Raven Publishers, Philadelphia © 1996 International Society for Neurochemistry Disposition of Histamine, Its Metabolites, and pros-Methylimidazoleacetic Acid in Brain Regions of Rats Chronically Infused with a-Fluoromethylhistidine George D. Prell, Erwin Douyon, William F. Sawyer, and Albert Marcus Morrishow Department of Pharmacology, Mount Sinai School of Medicine of the City University of New York, New York, New York, U.S.A. Abstract: In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), forming te/e-methylhistamine (t-MH), then tele- methylimidazoleacetic acid (t-MIAA). We previously showed that imidazoleacetic acid (IAA), a GABA agonist, and histamine’s metabolite in the periphery, is present in brain where its concentration increased after inhibition of HMT. Also, when [ 3H]histamine was given intracerebro- ventricularly to rats, a portion was converted to IAA, a process increased by inhibition of HMT. These results indicated that brain has the capacity to oxidize histamine but did not show whether this pathway is operative under physiological conditions. To address this question, rats were infused for >4 weeks with a-fluoromethylhistidine (a-FMHi5), an irreversible inhibitor of histamine’s syn- thetic enzyme, L-histidine decarboxylase. Compared with controls (untreated and saline-treated rats), brain levels of histamine, t-MH, and t-MIAA in all regions were mark- edly reduced in treated rats. As a percentage of controls, depletion of t-MIAA > t-MH > histamine in all regions, and regional depletions of histamine corresponded to its turnover rates in regions of rat brain. In contrast, levels of IAA were unchanged as were levels of pros-methylim- idazoleacetic acid, an isomer of t-M IAA unrelated to hista- mine metabolism. Results suggest that in brains of rats, unlike in the periphery, most IAA may not normally derive from histamine. Because histamine in brain can be con- verted to IAA under certain conditions, 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 a-FMHis infusion as a model to probe the histaminergic system in brain. Key Words: Histamine—Imidazoleacetic acid—Oxida- tion—a-Fluoromethylhistidine—Metabolite—pros-Meth- ylimidazoleacetic acid. J. Neurochem. 66, 21 53—21 59 (1996). Histamine is a central neurotransmitter (Schwartz et a!., 1991, 1995; Green, 1994). Its neurons project throughout brain from cell bodies in the posterior hy- pothalamus. Histamine stimulates two populations of postsynaptic membrane-bound receptors, H 1 and H2 its neuronal synthesis and release are regulated by an autoreceptor, H3 (see Schwartz and Haas, 1992). His- tamine is involved in several functions, including regu- lation of wakefulness, body temperature, blood pres- sure, pituitary hormone release, drinking, and release of other transmitters (Hough and Green, 1984; Schwartz et al., 1991, 1995; see Watanabe and Wada, 1991). Histamine in brain does not derive from hista- mine in plasma but is synthesized in situ from histidine by L-histidine decarboxylase (HD; EC 4.1.1.22), whose activity is highest in hypothalamus (Schwartz et al., 1970; Kishikawa et al., 1991). Once released, histamine is metabolized by histamine N-methyltrans- ferase (HMT; EC 2.1.1.8), localized postsynaptically (Bischoff and Korf, 1978), which forms tele-methyl- histamine (t-MH). The latter is oxidized by mono- amine oxidase (MAO; EC 1.4.3.4)-B and then by an aldehyde dehydrogenase (EC 1.2.1.-) to form tele- methylimidazoleacetic acid (t-MIAA) (Hough and Green, 1984; Schwartz et al., 1991; Watanabe et al., 1991; Green, 1994). We observed that imidazoleacetic acid (IAA), a me- tabolite of histamine in the periphery, is present in brain and CSF (Khandelwal et al., 1989; Prell and Morrishow, 1989). IAA is a GABA-A agonist (e.g., Swagel et al., 1973; Kemp et al., 1986) and a potent antioxidant (Hartman et al., 1990). It exerts many cen- trally mediated effects including analgesia, sedation, and reductions in blood pressure, body temperature, Received October 11, 1995; revised manuscript received Decem- ber 20, 1995; accepted January 2, 1996. Address correspondence and reprint requests to Dr. G. D. Prell at Department of Pharmacology (Box 1215), Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, NY 10029-6574, U.S.A. Abbreviations used: ANOVA, analysis of variance; DAO, cliamine oxidase; a-FMHis, (S)-a-fluoromethylhistidine; GCIMS, gas chro- matography—mass spectrometry; HD, L-hiStidine decarboxylase; EIMT, histamine N-methyltransferase; IAA, imidazoleacetic acid; MAO, monoamine oxidase; p-MIAA, pros-methylimidazoleacetic acid; t-MH, tele-methyihistamine; t-MIAA, tele-methylimidazole- acetic acid. 2153