The effects of some dopamine antagonists on cholinergic mechanisms in the guinea-pig ileum.

1. Activation of prejunctional muscarinic and opiate receptors on cholinergic neurones of the guinea-pig ileum by acetylcholine (ACh) or morphine was seen as an inhibition of twitch responses to transmural electrical stimulation. These inhibitory responses were antagonised by metoclopramide and DL308-IT but no other antagonist used blocked the morphine responses apart from sulpiride in very high concentrations (100 muM and above). 2 Prejunctional and postjunctional responses to ACh on the guinea-pig ileum were measured in the presence of increasing concentrations of some muscarinic and dopamine antagonists. Atropine, hyoscine, chlorpromazine, cis-flupenthixol and thioridazine showed no selectivity in their antagonism of either response to ACh. Benzhexol selectivity antagonised the postjunctional response whereas metoclopramide and DL308-IT showed greater selectivity for the prejunctional effect which they antagonised competitively. Sulpiride, a compound chemically related to metoclopramide, blocked neither the prejunctional nor postjunctional ACh responses. Clozapine antagonised the postjunctional ACh responses whilst apparently potentiating the prejunctional inhibition by ACh. 3 It was concluded that pharmacological differences may exist between prejunctional and postjunctional muscarinic receptors for ACh and that the antipsychotic actions of dopamine antagonists are unlikely to involve blockade of prejunctional ACh or opiate receptors.