In vivo modulation of rat hypothalamic histamine release by the histamine H3 receptor ligands, immepip and clobenpropit.: Effects of intrahypothalamic and peripheral application

We investigated the effect of the new potent and selective histamine H-3 receptor agonist, immepip, and the histamine H-3 receptor antagonist, clobenpropit, on in vivo neuronal histamine release from the anterior hypothalamic area of urethane-anesthetized rats, using microdialysis. Intrahypothalamic perfusion with immepip af:concentrations of 1 and 10 nM reduced histamine release to 75% and 35% of its basal level, respectively. Peripheral injection of immepip (5 mg/kg) caused a sustained decrease in histamine release of 50%. Clobenpropit potently increased histamine release after intrahypothalamic perfusion. The maximal increase in histamine release was 2-fold, observed at a concentration of 10 nM clobenpropit. Peripheral injection of clobenpropit (5-15 mg/kg) increased histamine release to about 150% of the basal value. A more marked increase in histamine release was found after injection of the histamine H-3 receptor antagonist, thioperamide (5 mg/kg). In conclusion, intrahypothalamic perfusion of the histamine H3 receptor agonist, immepip and the histamine H-3 receptor antagonist, clobenpropit, potently and oppositely modulated in vivo histamine release from the anterior hypothalamic area. The decreased histamine release after peripheral injection of immepip indicates that this novel agonist readily crosses the blood-brain barrier, making it a potential candidate for in vivo histamine H-3 receptor studies. The differential increase in histamine release after peripheral injection of clobenpropit and thioperamide is discussed. (C) 1998 Elsevier Science B.V. All rights reserved.