title: Microdialysis study of the effects of the antiparkinsonian drug budipine on L-DOPA-induced release of dopamine and 5-hydroxytryptamine by rat substantia nigra and corpus striatum.
abstract: The purpose of this study was to determine if systemic treatment with the antiparkinsonian drug budipine was capable of influencing the release of dopamine newly synthesised from L-DOPA in the substantia nigra and corpus striatum of the monoamine-depleted rat. Dual probe microdialysis was therefore employed in freely moving animals pretreated with reserpine (4 mg/kg i.p. 18-20 h earlier) and alpha-methyl-p-tyrosine (200 mg/kg i.p. 45 min earlier). Budipine (10 mg/kg i.p.) alone evoked a small but significant increase in basal dopamine efflux in nigra, though not in striatum, but did not affect the spontaneous outputs of DOPAC, 5-HT, or 5-HIAA in either structure. A threshold amount of L-DOPA (25 mg/kg i.p.) stimulated the release of dopamine, DOPAC, and 5-HT (but not 5-HIAA), both in nigra and striatum. The L-DOPA-induced releases of dopamine and DOPAC were greatly accentuated by pretreatment with budipine (10 mg/kg i.p. 45 min earlier), which delayed rather than potentiated the nigral and striatal effluxes of 5-HT. A higher dose of L-DOPA (100 mg/kg i.p.) did not significantly raise the outputs of dopamine or 5-HT, but greatly magnified that of DOPAC. In these experiments, pretreatment with budipine (10 mg/kg i.p.) facilitated the formation of DOPAC from L-DOPA, without increasing the extracellular concentration of dopamine. We conclude from these findings that budipine, at a therapeutically relevant dose, potentiates the release of dopamine newly synthesised from L-DOPA from either end of the nigrostriatal dopamine axis. This effect of budipine could be related to the drug's recently described ability to increase the activity of the converting enzyme, aromatic L-amino acid decarboxylase, and could explain the clinical efficacy of budipine as an adjunct to L-DOPA therapy of Parkinson's disease in man. The significance of 5-HT release to the antiparkinsonian L-DOPA, and the delay in this release caused by budipine, remain to be established.
authors.affiliation: Department of Pharmacology, The School of Pharmacy, London, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Biggs
authors.forename: M S
authors.initials: MS
authors.lastname: Starr
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019805:alpha-Methyltyrosine / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000978:Antiparkinson Agents; D010880:Piperidines; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D007980:Levodopa; D019805:alpha-Methyltyrosine; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; C026710:budipine; D004298:Dopamine