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

Abstract

Abstract. The H 3 antagonist thioperamide is thought to act on brain H 3 autoreceptors to increase both the release and metabolism of neuronal histamine (HA). Our studies investigated the effects of several new brain-penetrating H 3 antagonists on rat cerebral cortical levels of the HA metabolite tele-methylhistamine ( 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 inhibitor pargyline to prevent metabolism of t-MH. Cortical t-MH levels were measured by both radioimmunoassay (RIA) and gas chromatography–mass spectrometry (GC–MS). Pargyline (60 mg/kg; 1 hr; i.p.) produced an ∼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 GC–MS and RIA. In contrast, neither 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT-2016) (± pargyline), 4-(6-cyclohexylhex- cis-3enyl)imidazole (GT-2227) (± pargyline), nor clobenpropit (minus pargyline) increased t-MH levels as measured by GC–MS. A good agreement was found between t-MH levels as determined by either RIA or GC–MS except after treatment with GT-2016, which increased apparent t-MH brain levels according to the former but not the latter method. Subsequent studies suggest the in vivo formation of a GT-2016 metabolite, 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, only 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, partial agonist, or antagonist in vivo activity.