The antagonistic effect of neuroleptics to acetylcholine, histamine, 5-HT, and noradrenaline was examined in various in vivo and in vitro models. Piflutixol, a new potent thioxanthene neuroleptic, markedly antagonizes the effect of dopamine, noradrenaline, 5-HT and to some extent histamine, whereas the affinity for muscarinic receptors was rather weak. Clozapine and chlorprothixene on the other hand, have high affinity for muscarinic receptors and also antagonize the effect of histamine and 5-HT, whereas clozapine was a weak antagonist of noradrenaline and dopamine when compared to the effect of piflutixol. Chlorprothixene, however, also exhibits a rather good antagonism of noradrenaline and dopamine. Haloperidol proved to be weak in all models when compared with the other neuroleptics examined. Flupenthixol specifically antagonizes dopamine and noradrenaline, whereas fluphenazine was a more potent antagonist of dopamine than of the other transmitters. The data show, that neuroleptic compounds possess very different profiles with regard to interaction with various neurotransmitter substances. It is suggested, that the rather potent anti 5-HT and antihistamine effects observed for certain substances may contribute to the central effect of these drugs.
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