Neuropeptidases as sites of peptide regulation by dopaminergic drugs
AdvisorDavis, Thomas P.
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PublisherThe University of Arizona.
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AbstractAntipsychotic drugs have been previously shown to affect the level and mRNA of specific neuropeptides. The effects of these drugs on the activity and function of peptide-degrading enzymes, or neuropeptidases, have not been systematically characterized. In the present studies, the effects of antipsychotics and other dopaminergic drugs on the degradation of neuropeptides that regulate dopamine neurons, activity of specific neuropeptidases and levels of neuropeptidase mRNA in rat brain regions were determined. Subchronic (7 day) administration of the antipsychotic and dopamine receptor antagonists, haloperidol (1 mg/kg) and chlorpromazine (20 mg/kg) regionally decreased whereas the dopamine receptor agonist, apomorphine (5 mg/kg, every 12 hr), increased the degradation of substance P and met-enkephalin on intact, rat brain slices. Cholecystokinin degradation was not affected by any drug treatment studied. Studies performed with specific neuropeptidase inhibitors provided evidence that neutral endopeptidase 24.11, aminopeptidase N, metalloendopeptidase 24.15 and angiotensin converting enzyme degrade substance P and/or met-enkephalin and may be affected in vivo by dopaminergic drug treatment. Therefore, the activity of these neuropeptidases was determined using specific enzyme assays on regional, P2 membranes after drug administration. Subchronic administration of haloperidol and apomorphine differentially affected the activity of aminopeptidase N and neutral endopeptidase 24.11. The activity of metalloendopeptidase 24.15 and angiotensin converting enzyme was largely unaffected by experimental treatments. Determination of the molecular mechanism of the drug-induced alterations in aminopeptidase N and neutral endopeptidase 24.11 activity was attempted by analyzing neuropeptidase mRNA levels. RNase protection assays showed only an increase in aminopeptidase N mRNA in the caudate-putamen after apomorphine administration, where the largest drug-induced alteration in neuropeptidase activity was also observed. Therefore, changes in neuropeptidase gene transcription may play a role in altered neuropeptidase activity. However, it is likely that alterations in post-transcriptional events have a larger role in the effects observed during the present studies. The present work demonstrates further alterations in neuropeptide systems induced by drugs that interact with dopaminergic receptors. In view of the regulatory actions of neuropeptides on dopamine neurons, alterations in the activity and function of neuropeptidases, and thus neuropeptide degradation can, in turn, play a role in modulating brain dopaminergic activity.
Degree ProgramGraduate College
Pharmacology and Toxicology