Central antiemetic actions of pimozide and haloperidol in the dog

Abstract

The effect of pimozide and haloperidol against emesis induced by nine agents, whose sites of action in producing vomiting have been clearly demonstrated, were studied in conscious dogs. Pimozide and haloperidol were extremely effective in preventing apomorphine-induced emesis. The 50% protective dose (PD50) of oral and intracerebroventricular (4th ventricle) pimozide against emesis, induced by 0.01mg/kg (threshold dose) of intravenous apomorphine, was 5 μg/kg and 0.3 ng/kg, respectively. The corresponding PD50 for haloperidol was 10 smg/kg orally and 0.3 ng/kg via the 4th ventricle. With an oral dose of 100 μg/kg, pimozide and haloperidol prevented emesis induced by a threshold dose of apomorphine for an average of 6.6 and 4.2 days, respectively. Oral administration of 1 mg/kg of pimozide and haloperidol completely inhibited emesis induced by levodopa or Hydergine. The same dose of either pimozide or haloperidol afforded moderate protection against emesis induced by copper sulfate, but had no effect on emesis induced by Veriloid or pilocarpine. These findings indicate that the primary site of antiemetic actions of pimozide and haloperidol is on the chemoceptive emetic trigger zone in the area postrema of the medulla oblongata. At higher doses, however, depression of the vomiting center in the reticular formation of the medulla may also contribute to their antiemetic activity. Furthermore, pimozide afforded only moderate protection against vomiting induced by morphine while haloperidol was ineffective. Both agents were ineffective against emesis induced by ouabain or acetylstrophanthiclin. Since these latter emetic agents act principally through the trigger zone, this may imply that either the affinity of these agents at the receptor site is different, or these agents act at different receptor sites within the trigger zone.