Agonist--antagonist interaction on dopamine receptors in brain, as reflected in the rates of tyrosine and tryptophan hydroxylation.
The effect of haloperidol and apomorphine, and both drugs in combination, on the first steps in the synthesis of catecholamines and 5-hydroxytryptamine (5-HT) has been studied in three rat brain regions. The rate of formation of dopa and 5-hydroxytryptophan (5-HTP) was studied by measuring the accumulation of these amino acids during 30 min after administration of the inhibitor of the aromatic L-amino acid decarboxylase, NSD 1015 (3-hydroxybenzylhydrazine HCl). Haloperidol caused an increase in dopa and no change in 5-HTP formation. The threshold dose was severalfold higher in the noradrenaline-predominated hemisphere portion than in the dopamine-rich striatal and limbic regions, suggesting a higher affinity of haloperidol for dopamine than for noradrenaline receptors. Apomorphine caused a decrease in dopa formation in all three brain regions studied, although the effect was much more pronounced in the regions dominated by dopamine. The threshold dose was about 30 microng/kg, i.e. an order of magnitude lower than the threshold dose for apparent postsynaptic dopaminergic receptor activation. This discrepancy is suggested to be due to preferential activation of inhibitory dopaminergic autoreceptors by low apomorphine doses. This phenomenon may also contribute to explain the complex dose-response curves of apomorphine. Low doses of apomorphine caused a decrease and high doses an increase in 5-HTP formation. These effects, like those on noradrenaline synthesis, are suggested to be secondary to activation of dopaminergic pre- and post-synaptic receptors. The interaction between apomorphine and haloperidol with respect to dopa formation appears to be largely explicable on the assumption of a competition between an agonist and an antagonist for dopaminergic receptors. However, very large doses of apomorphine cause a haloperidol-resistant inhibition of tyrosine, and probably also tryptophan, hydroxylation, which may be due to a direct inhibition of the aromatic amino acid hydroxylase involved.
D006916:5-Hydroxytryptophan / Q000096:biosynthesis*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology*; D008032:Limbic System / Q000378:metabolism; D008297:Male; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D013687:Telencephalon / Q000378:metabolism
D011954:Receptors, Dopamine; D004295:Dihydroxyphenylalanine; D006916:5-Hydroxytryptophan; D006220:Haloperidol; D001058:Apomorphine