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EVIDENCE FOR AN INHIBITORY PRESYNAPTIC COMPONENT OF NEUROLEPTIC DRUG ACTION
Author(s) -
BELLEROCHE J.S.,
BRADFORD H.F.
Publication year - 1981
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1981.tb10993.x
Subject(s) - fluphenazine , haloperidol , dopamine , thioridazine , pharmacology , chlorpromazine , chemistry , inhibitory postsynaptic potential , mechanism of action , endocrinology , in vitro , medicine , biochemistry
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 [ 14 C]‐dopamine from l ‐[U‐ 14 C]‐tyrosine and a decrease in the tissue content of [ 14 C]‐dopamine, with IC 50 values for the latter effect ranging from 3.6 × 10 −7 to 5.9 × 10 − 5 m . The rank order of their potency was similar to the order of their clinical effectiveness: haloperidol>fluphenazine> cis ‐flupenthixol>chlorpromazine>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 concentrations 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 [ 14 C]‐dopamine from subsequently prepared synaptosomes. A marked inhibition of the K + ‐induced increase in [ 14 C]‐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 [ 14 C]‐dopamine and reduced the K + ‐induced increase in release of [ 14 C]‐dopamine. 5 Cis ‐flupenthixol at a dose of 20 mg/kg reduced the K + ‐induced release of [ 14 C]‐dopamine by 48% and to a lesser extent, that of γ‐aminobutyric acid (GABA, 25%). 6 An inhibitory mode of action is proposed for neuroleptics mediated through a presynaptic mechanism.