HALOPERIDOL AND APOMORPHINE DIFFERENTIALLY AFFECT NEUROPEPTIDASE ACTIVITY

In addition to their well characterized effects at dopamine receptors, neuroleptic drugs have been shown to affect the level and in vitro me tabolism of neuropeptides. In the present study, the effect of acute a nd subchronic administration of the neuroleptic haloperidol and the no nselective, dopamine agonist apomorphine on neuropeptidase activity wa s determined in regional, rat brain P-2 membranes. Subchronic administ ration of haloperidol decreased the activity of aminopeptidase N in th e frontal cortex and caudate-putamen. In contrast, subchronic administ ration of apomorphine increased aminopeptidase N activity in the front al cortex and caudate-putamen, Neutral endopeptidase 24.11 also was af fected differentially in the caudate-putamen, but both subchronic halo peridol and apomorphine decreased neutral endopeptidase 24.11 activity in the frontal cortex, Metalloendopeptidase 24.15 activity was decrea sed in the caudate-putamen after acute haloperidol and increased in th e frontal cortex after acute apomorphine administration; however, no e ffect was noted after subchronic administration of either drug. Angiot ensin converting enzyme was not affected by any treatment. Therefore, neuroleptic-induced alterations in aminopeptidase N, neutral endopepti dase 24.11 and metalloendopeptidase 24.15 activity may account for pre viously reported alterations in neuropeptide degradation. In view of t he interaction between mesocorticolimbic dopamine neurons and neuropep tides, e.g., substance P, neurotensin and enkephalins, neuroleptic-ind uced alterations in the activities of neuropeptidases, and thus neurop eptide metabolism can, in turn, play a role in modulating midbrain dop aminergic activity.