Effect of tolcapone, a catechol- O-methyltransferase inhibitor, on striatal dopaminergic transmission during blockade of dopamine uptake

To examine the mechanisms of tolcapone in the central nervous system (CNS), we analyzed alterations in parameters of striatal dopamine transmission induced by this drug (30 mg/kg) co-administered with the selective dopamine uptake inhibitor, GBR 12909 (10 mg/kg). Using microdialysis in freely moving...

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Bibliographic Details
Published in:European journal of pharmacology 1999-04, Vol.370 (2), p.125-131
Main Authors: Budygin, Evgeny A, Gainetdinov, Raul R, Kilpatrick, Michaux R, Rayevsky, Kirill S, Männistö, Pekka T, Wightman, R.Mark
Format: Article
Language:English
Subjects:
Animals
Benzophenones - pharmacology
Catechol O-Methyltransferase Inhibitors
Corpus Striatum - drug effects
Corpus Striatum - metabolism
Dopamine - biosynthesis
Dopamine - metabolism
Dopamine release
Dopamine synthesis
Dopamine uptake
Dopamine Uptake Inhibitors - pharmacology
Drug Interactions
Electric Stimulation
Enzyme Inhibitors - pharmacology
GBR 12909
Injections, Intraperitoneal
Male
Microdialysis
Nitrophenols
Piperazines - pharmacology
Rats
Rats, Sprague-Dawley
Stereotyped Behavior - drug effects
Synaptic Transmission - drug effects
Tolcapone
Voltammetry, cyclic
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Summary:To examine the mechanisms of tolcapone in the central nervous system (CNS), we analyzed alterations in parameters of striatal dopamine transmission induced by this drug (30 mg/kg) co-administered with the selective dopamine uptake inhibitor, GBR 12909 (10 mg/kg). Using microdialysis in freely moving rats, it was determined that combined administration of tolcapone with GBR 12909 resulted in a further increase of dopamine levels over that obtained without the catechol- O-methyltransferase inhibitor, while tolcapone alone failed to change dopamine levels. Fast-scan cyclic voltammetric monitoring of electrically evoked dopamine did not show any changes in dopamine release after the combination of the drugs, but there was a pronounced decrease in the rate of dopamine clearance after GBR 12909 alone and when co-administered with tolcapone. These data indicate that in rat striatum, a tolcapone-induced increase in extracellular dopamine is not observed because of the presence of uptake. These results also support the hypothesis that under normal conditions, uptake, rather than metabolism, control extracellular levels of dopamine.
ISSN:0014-2999
1879-0712
DOI:10.1016/S0014-2999(99)00084-9