Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors.
An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.
D015107:4-Butyrolactone / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D002090:Butyrophenones / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004347:Drug Interactions; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010640:Phenothiazines; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
D014150:Antipsychotic Agents; D002090:Butyrophenones; D010640:Phenothiazines; D011954:Receptors, Dopamine; D001058:Apomorphine; D015107:4-Butyrolactone; D004298:Dopamine