Effects of selected histamine H-3 receptor antagonists on tele-methylhistamine levels in rat cerebral cortex

The H-3 antagonist thioperamide is thought to act on brain H-3 autoreceptor s to increase both the release and metabolism of neuronal histamine (HA). O ur studies investigated the effects of several new brain-penetrating H-3 an tagonists on rat cerebral cortical levels of the HA metabolite tele-methylh istamine (t-MH). Animals were pretreated with H-3 antagonists (0.3 to 30 mg /kg; 1-4 hr; i.p.) in the presence or absence of the monoamine oxidase inhi bitor pargyline to prevent metabolism of t-MH. Cortical t-MH levels were me asured by both radioimmunoassay (RIA) and gas chromatography-mass spectrome try (GC-MS). Pargyline (60 mg/kg; 1 hr; i.p.) produced an similar to 2-fold increase in t-MH levels as measured by either GC-MS or RIA. Thioperamide ( +/- pargyline) increased t-MH levels as measured by both CC-MS and RIA. In contrast, neither 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT -2016) (+/- pargyline), 4-(6-cyclohexylhex-cis-3-enyl) imidazole (GT-2227) (+/- pargyline), nor clobenpropit (minus pargyline) increased t-MH levels a s measured by GC-MS. A good agreement was found between t-MH levels as dete rmined by either RIA or CC-MS except after treatment with GT-2016, which in creased apparent t-MH brain levels according to the former but not the latt er method. Subsequent studies suggest the in vivo formation of a GT-2016 me tabolite, which can cross-react in the t-MH RIA. Although all H-3 receptor antagonists studied to date seem capable of enhancing brain HA release, onl y thioperamide presently was found to enhance cortical t-MH levels. Thus, H -3 receptor antagonists may differentially affect HA release and turnover, and brain t-MH levels may not be reliable predictors of H-3 agonist, partia l agonist, or antagonist in vivo activity. (C) 1999 Elsevier Science Inc.