Metoclopramide and dopamine receptor blockade

Metoclopramide produced a dose-dependent increase in striatal and mesolimbic homovanillic acid concentrations in mice. Dihydroxyphenylacetic acid levels were only elevated at high dosage levels. Metoclopramide accelerated cerebral dopamine disappearance following pretreatment with α-methyl-p-tyrosine and caused an increased accumulation of whole brain dihydroxyphenylalanine (DOPA) following pretreatment with NSD 1034. All this evidence suggests that metoclopramide blocks cerebral dopamine receptors causing increased turnover of dopamine. Chronic administration of metoclopramide produced a reduction in its effect on homovanillic acid levels as was observed following chronic haloperidol treatment. However, metoclopramide had no effect on the in vitro dopamine-stimulated adenylate cyclase system of the rat striatum. Unilateral striatal injection of metoclopramide, on the other hand. produced ipsiversive turning behaviour in response to systemically administered apomorphine, indicating a direct mode of action. This evidence suggests that metoclopramide causes a blockade of dopamine receptors by a mechanism differing from that of classical neuroleptics.