Comparison of the effects of neuroleptic drugs on pre and postsynaptic dopaminergic mechanisms in the rat striatum

L. L. Iversen, M. A. Rogawski, R. J. Miller

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Neuroleptic drugs of various chemical classes were compared as inhibitors of the postsynaptic dopamine sensitive adenylate cyclase in rat striatum and for their ability to influence a variety of presynaptic mechanisms in dopaminergic nerve terminals in striatum. Sixteen chemical analogues of the butyrophenone haloperidol were tested on the dopamine sensitive adenylate cyclase, and the results showed a good correlation between inhibitory potency in this system and the known effects of these compounds as apomorphine antagonists in vivo. In intact synaptosome preparations from rat striatum apomorphine was a potent inhibitor (IC50 = 0.2 μM) of the conversion of tritiated tyrosine to catechols. Other dopamine mimetic drugs [epinine, dopamine, 2 amino 6,7 dihydroxy 1,2,3,4 tetrahydronaphthalene (ADTN) also had similar inhibitory effects, although the alpha adrenoceptor agonist phenylephrine and the beta agonist isoprenaline were also inhibitory at higher concentrations. The inhibitory actions of dopamine, epinine, ADTN, and noradrenaline were significantly reduced by addition of the dopamine uptake inhibitor benztropine, suggesting that they act at least in part by inhibition of intrasynaptosomal tyrosine hydroxylase after uptake into dopaminergic terminals. The effects of apomorphine, however, were unaffected by benztropine, suggesting a direct action on presynaptic 'autoreceptors' at dopaminergic terminals. All the compounds tested were at least 50 times less potent as inhibitors of free tyrosine hydroxylase in detergent containing striatal homogenates. The inhibitory effects of apomorphine on synaptosomal catechol synthesis were partially reversed by various neuroleptic drugs, and this appeared to be due to a competitive interaction between the neuroleptic drugs and apomorphine at presynaptic receptor sites. The neuroleptics, however, also tended themselves to inhibit catechol synthesis when added alone. Haloperidol, spiroperidol, and pimozide were particularly potent in reversing the presynaptic actions of apomorphine on catechol formation, being active at concentrations between 10 and 100 nM. Neuroleptics also had some activity as inhibitors of [3H]dopamine uptake and as dopamine releasers in striatal synaptosomes. They also antagonized the evoked release of [3H]dopamine elicited by protoveratrine. None of these effects, however, occurred at very low drug concentration, and the butyrophenones were no more potent than chlorpromazine. It is concluded that neuroleptics possess actions on both pre and postsynaptic sites in the striatum, but that the postsynaptic blocking action on dopamine receptors is likely to be most crucial for the clinical activity of these drugs.

Original languageEnglish (US)
Pages (from-to)251-262
Number of pages12
JournalMolecular Pharmacology
Volume12
Issue number2
StatePublished - Dec 1 1976

ASJC Scopus subject areas

  • Pharmacology

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