Ivan Donaldson

Metoclopramide and dopamine receptor blockade.

Abstract 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.

The roles of noradrenaline and dopamine in contraversive circling behaviour seen after unilateral electrolytic lesions of the locus coeruleus

Unilateral electrolytic lesions of the locus coeruleus in rats result in spontaneous ipsiversive rotation, which is then replaced by contraversive rotation. One week after lesioning, when spontaneous turning ceases, apomorphine and d-amphetamine elicit contraversive circling behaviour, which was not affected by noradrenergic receptor blockade but was abolished by dopamine receptor blockade. The drug-induced contraversive circling response was also reproduced by piribedil but not clonidine. Combined unilateral electrolytic locus coeruleus and substantia nigra lesions on the same side resulted in apomorphine- and d-amphetamine-induced ipsilateral rotational behaviour which was indistinguishable from that seen with substantia nigra lesions alone. In rats with unilateral locus coeruleus lesions, the dose of intrastriatally injected apomorphine required to produce circling was less on the lesioned than the non-lesioned side. Direct injection of noradrenaline into one substantia nigra caused contraversive circling. Direct injection of phenoxybenzamine into one substantia nigra followed by apomorphine caused ipsiversive circling. The results suggest that the circling behaviour seen after unilateral locus coeruleus lesions depends on an asymmetry of striatal dopamine receptor activity and are consistent with a proposed coeruleus-nigral noradrenergic pathway, which enhances impulse flow in the dopaminergic nigrostriatal system.