Effect of tolcapone, a catechol-O-methyltransferase inhibitor, on striataldopaminergic 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 in duced by this drug (30 mg/kg) co-administered with the selective dopamine u ptake 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 releas e after the combination of the drugs, but there was a pronounced decrease i n the rate of dopamine clearance after GBR 12909 alone and when co-administ ered with tolcapone. These data indicate that in rat striatum, a tolcapone- induced increase in extracellular dopamine is not observed because of the p resence of uptake. These results also support the hypothesis that under nor mal conditions, uptake, rather than metabolism, control extracellular level s of dopamine. (C) 1999 Elsevier Science B.V. All rights reserved.