Microdialysis studies on the action of tolcapone on pharmacologically-elevated extracellular dopamine levels in conscious rats

To elucidate the importance of catechol-O-methyltransferase, we performed s triatal microdialysis studies in conscious rats given tolcapone, an inhibit or of catechol-O-methyltransferase, together with four compounds each of wh ich elevates the extracellular dopamine content through a different mechani sm. Tolcapone itself did not alter dopamine levels in the striatal microdia lysis fluid but increased DOPAC and decreased homovanillic acid levels. How ever, tolcapone pie treatment (30 mg/kg) multiplied the already high dopami ne levers after levodopa, and less so the moderately elevated dopamine leve ls after GBR-12909 (at 20 mg/kg) alone, but the minor (insignificant) dopam ine-elevating effects of haloperidol and (+)-U232 were not altered. In all cases, a tolcapone pretreatment decreased homovanillic acid levels and elev ated DOPAC levers. In further combination studies, GBR-12909 did not alter significantly the effects of levodopa/carbidopa on dopamine, DOPAC and homo vanillic acid levels. In these rats, tolcapone enhanced the effect of GBR-1 2909 on extracellular dopamine but not on DOPAC. In conclusion, when levodo pa and carbidopa are given together, COMT inhibition becomes extremely mean ingful, and dopamine levels are multiplied by tolcapone. Otherwise, tolcapo ne is able to further elevate extracellular dopamine levels only when dopam ine turnover is normal or low but not when it is high. Overall, the role of COMT in the elimination of synaptic dopamine remains minor compared to the dominance of the reuptake process.