Evidence for an inhibitory presynaptic component of neuroleptic drug action.

1 The action of five neuroleptic drugs (haloperidol, cis-flupenthixol, chlorpromazine, fluphenazine and thioridazine) was studied on the synthesis and release of dopamine from rat striatal synaptosomes. 2. In vitro application of the drugs induced an inhibition of synthesis of [14C]-dopamine from L-[U-14C]-tyrosine and a decrease in the tissue content of [14-C]-dopamine, with IC50 values for the latter effect ranging from 3.6 x 10(-7) to 5.9 x 10(-5) M. The rank of their potency was similar to the order of their clinical effectiveness: haloperidol greater than fluphenazine greater than cis-flupenthixol greater than chlorpromazine greater than thioridazine. Trans flupenthixol was without effect up to a concentration of 10(-4) M. 3 The tissue level and release of GABA were not affected by concentration of the neuroleptics up to 10(-4) M. 4 When the neuroleptics were administered in vivo, changes were also detected in the synthesis and release of [14C-]-dopamine from subsequently prepared synaptosomes. A marked inhibition of the K+-induced increase in [14C]-dopamine synthesis was seen following a dose of 2 mg/kg cis-flupenthixol and haloperidol. At this concentration, haloperidol also increased the control release of [14C]-dopamine and reduced the K+-induced increase in release of [14C]-dopamine. 5 Cis-flupenthixol at a dose of 20 mg/kg reduced the K+-induced release of [14C]-dopamine by 48% and to a lesser extent, that of gamma-aminobutyric acid (GABA, 25%). 6 An inhibitory mode of action is proposed for neuroleptics mediated through a presynaptic mechanism.