Effect of dopaminergic drugs on processing and degradative neuropeptidase mRNA in rat frontal cortex and caudate-putamen

Drugs which act upon central dopamine receptors alter the level, mRNA expression and in vitro degradation of neuropeptides associated with dopamine neuron regulation. Changes in the degradation of certain neuropeptides are correlated with significant alterations in the activity of specific neuropeptidases, namely aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP 24.11). In the present study, we sought to examine the molecular mechanism of neuropeptidase activity changes in response to dopaminergic drug treatment. The effects of dopaminergic drugs on the mRNA level of APN and NEP 24.11 were determined by RNase protection assays of RNA extracted from rat frontal cortex and caudate-putamen. Additionally, the effects of dopaminergic drugs on the mRNA expression for the neuropeptide processing enzymes, prohormone convertase 1 (PC1) and PC2, were determined. After 7-day administration of the dopamine receptor antagonist, haloperidol (1 mg/kg), no effect on the mRNA expression of APN, NEP 24.11, PC1 or PC2 was observed in either of the rat brain regions studied. Administration of the dopamine receptor agonist, apomorphine (5 mg/kg, bid), altered only the expression of APN mRNA in rat caudate-putamen, where the greatest effect on APN activity has been previously observed. These results suggest that alterations in other post-transcriptional events, such as mRNA translation or insertion of neuropeptidase protein into the membrane, likely play a larger role than changes in mRNA expression in the modulation of neuropeptidase activity.