Neuropharmacological comparison between domperidone and metoclopramide.

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Abstract
Domperidone, a new gastrokinetic with potent antiemetic properties, is devoid of central effects, up to high dose levels. To assess the CNS activity of domperidone and metoclopramide, the inhibition of intracranial self-stimulation (ICS) in 2 different situations and the influence on EEG in dogs were studied. The dissociation between the antiemetic and central effects of both compounds was evaluated in dogs given a stereotypogenic dose of apomorphine. A significant and dose-related inhibition of ICS (conditioned situation) was obtained with 0.8 and 1.6 mg/kg i.v. domperidone and with 0.125, 0.25 and 0.50 mg/kg i.v. metoclopramide. The ED50 values were 0.79 and 0.25 mg/kg, respectively. The effect was most pronounced 4 h after administration with domperidone and 15 min after administration with metoclopramide. In the EEG studies, no specific structure-related effects were found but the total potency was increased with domperidone 0.8 and 1.6 mg/kg i.v. and with metoclopramide 0.063, 0.125, 0.25 and 0.50 mg/kg i.v. This increase was due to a decrease in fast frequencies, an increase of slower frequencies and a slight increase of the amplitude. Sleep-like patterns were not observed with either compound. In the apomorphine-test in dogs, the ratio between the i.v. ED50 values for antagonism of stereotypy and of emesis was 180 (1.8/0.01) for domperidone and 2.67 (0.64/0.24) for metoclopramide. Thus, central effects and antiemetic effects are concomitant with metoclopramide, whereas with domperidone, extremely large doses are required to obtain central effects.