The antiparkinsonian drug budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra.
The present study examined the effects of the antiparkinsonian drug budipine on dopamine synthesis and release from L-DOPA in the substantia nigra of reserpine-treated rats. Budipine (at 100 microM, but not 10 microM) applied by reverse dialysis to the nigra caused a small and significant rise in dopamine recovery in normal rats, but not in rats pretreated with reserpine (4 mg/kg i.p. for 18 hours) and alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg i.p. for 1 hour to limit dopamine synthesis to L-DOPA). L-DOPA applied to the nigra by reverse dialysis in reserpine + alpha-MPT-treated rats, increased the recovery of dopamine when applied at 5 or 10 microM, but not at 2 microM. Coadministration of budipine (10 microM) significantly enhanced L-DOPA-induced dopamine (and DOPAC) release with 5 microM L-DOPA, but not with 2 or 10 microM L-DOPA. This potentiation was even more pronounced when the budipine concentration was raised to 100 microM (equivalent to approximately 10 microM extracellularly). Pretreating rats with budipine (5, 12.5, or 20 mg/kg i.p.) for 1 hour significantly raised the activity of the enzyme L-aromatic amino acid decarboxylase in the striata and nigras of intact rats, as well as in rats pretreated with reserpine alone (5 mg/kg i.p.), without altering tissue levels of dopamine or its metabolites. It is suggested that the beneficial effects of budipine, when used as an adjunct to L-DOPA therapy of Parkinson's disease, may be due to an increase in the bioconversion of L-DOPA with a consequent rise in synaptic dopamine. These actions of budipine may be related to its weak NMDA receptor antagonist property.
Department of Pharmacology, The School of Pharmacy, London, United Kingdom.
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Biggs
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Fisher
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D007700:Kinetics; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D000978:Antiparkinson Agents; D010880:Piperidines; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D019805:alpha-Methyltyrosine; D012110:Reserpine; D001142:Aromatic-L-Amino-Acid Decarboxylases; C026710:budipine; D004298:Dopamine