NEUROPEPTIDE METABOLISM ON INTACT, REGIONAL BRAIN-SLICES - EFFECT OF DOPAMINERGIC AGENTS ON SUBSTANCE-P, CHOLECYSTOKININ AND MET-ENKEPHALINDEGRADATION

Neuroleptic drugs have been shown to affect the level and messenger ri bonucleic acid of specific neuropeptides. The effect of subchronically administered neuroleptics on neuropeptide metabolism, however, has no t been systematically characterized, in the present study, the effect of neuroleptics and other dopaminergic compounds on substance P (SP), cholecystokinin and met-enkephalin degradation was determined on intac t, regional, rat brain slices. After 7-day administration of haloperid ol (1 mg/kg) or chlorpromazine (20 mg/kg), SP degradation was decrease d in caudate-putamen and nucleus accumbens. After administration of th e dopaminergic agonist apomorphine (5 mg/kg, b.i.d,), SP degradation w as increased in the nucleus accumbens. The dopamine D-2-receptor antag onist sulpiride (100 mg/kg, b.i.d.) produced no effect on SP degradati on. Met-enkephalin degradation was decreased after haloperidol adminis tration in both frontal cortex and caudate-putamen acid unaffected by apomorphine administration. The metabolism of cholecystokinin was not affected by neuroleptic treatment. Studies performed with specific pep tidase inhibitors suggested that neutral endopeptidase 24.11, metalloe ndopeptidase 24.15 and aminopeptidases degrade SP on caudate-putamen a nd nucleus accumbens slices. Therefore, alterations in these peptidase s may be responsible for the change noted in SP degradation after dopa minergic compound administration. These metabolic changes noted after neuroleptic administration may therefore contribute to neuroleptic-ind uced alterations in regional peptide levels.