tolcapone and vanoxerine

6-Nitronoradrenaline, a bioactive compound recently identified in the brain, is known to inhibit catechol-O-methyltransferase. To study its effect on dopamine metabolism, it was administered into rat striatum via a microdialysis probe. Other nitrated catechols (6-nitrodopamine, 6-nitro-DOPAC and 5-nitro-HVA) were studied for comparison. Tolcapone, a selective catechol-O-methyltransferase inhibitor, was used as a positive reference compound. Both 6-nitronoradrenaline and tolcapone increased striatal extracellular dopamine levels during the perfusion (at 100 microM concentration but not at 10 microM) and decreased the efflux of homovanillic acid. Tolcapone, but not other nitrated catechols, increased 3,4-dihydroxyphenylacetic acid efflux. None of the compounds inhibited MAO-B activity at 100 microM or lower. At 1 mM, 6-nitrodopamine inhibited MAO-B by 60%. Compared to tolcapone, other nitrated catechols were very weak COMT inhibitors in vitro. Neither tolcapone nor 6-nitronoradrenaline modified the metabolism of L-dopa which was given peripherally. In binding studies, both 6-nitronoradrenaline and other nitrocatechols failed to affect the dopamine transporter even at high micromolar concentrations. In conclusion, exogenous 6-nitronoradrenaline can act as a COMT inhibitor in the striatum and elevate striatal dopamine levels without inhibiting dopamine reuptake. Whether endogenous 6-nitronoradrenaline can be formed also in vivo in the striatum and act as a regulator of dopaminergic tone remains to be determined.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benzophenones; Binding, Competitive; Carrier Proteins; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Extracellular Space; Homovanillic Acid; Male; Membrane Glycoproteins; Membrane Transport Proteins; Microdialysis; Monoamine Oxidase; Neostriatum; Nerve Tissue Proteins; Neurons; Nitric Oxide; Nitrophenols; Norepinephrine; Piperazines; Rats; Rats, Wistar; Tolcapone

Inhibition of catechol-0-methyltransferase (COMT) activity by Tolcapone was shown to result in increase of the striatal DA extracellular content in unrestrained rats pretreated with L-3,4-dihydroxyphenilalanine combined with Carbidopa, the decarboxylation inhibiting agent. Tolcapone enhanced the increase of the DA level in the rat striatal dialysates produced by treatment of these animals with specific DA re-uptake blocker GBR 12909. The latter elicits stereotype behaviour in rats that is substantially enhanced by tolcapone. The DA turnover rate in the striatum was decreased by the GBR 12909. The data obtained suggest that the DA transporter of neuronal membrane plays a major role in the neurochemical homeostasis at synaptic level.

Topics: Animals; Benzophenones; Carrier Proteins; Catechol O-Methyltransferase Inhibitors; Corpus Striatum; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Drug Interactions; Enzyme Inhibitors; Levodopa; Male; Membrane Glycoproteins; Membrane Transport Proteins; Microdialysis; Nerve Tissue Proteins; Nitrophenols; Piperazines; Rats; Rats, Wistar; Stereotyped Behavior; Synaptic Transmission; Tolcapone

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.

Topics: Animals; Benzophenones; Catechol O-Methyltransferase Inhibitors; Corpus Striatum; Dopamine; Dopamine Uptake Inhibitors; Drug Interactions; Electric Stimulation; Enzyme Inhibitors; Injections, Intraperitoneal; Male; Microdialysis; Nitrophenols; Piperazines; Rats; Rats, Sprague-Dawley; Stereotyped Behavior; Synaptic Transmission; Tolcapone

To elucidate the importance of catechol-O-methyltransferase, we performed striatal microdialysis studies in conscious rats given tolcapone, an inhibitor of catechol-O-methyltransferase, together with four compounds each of which elevates the extracellular dopamine content through a different mechanism. Tolcapone itself did not alter dopamine levels in the striatal microdialysis fluid but increased DOPAC and decreased homovanillic acid levels. However, tolcapone pretreatment (30 mg/kg) multiplied the already high dopamine levels after levodopa, and less so the moderately elevated dopamine levels after GBR-12909 (at 20 mg/kg) alone, but the minor (insignificant) dopamine-elevating effects of haloperidol and (+)-U232 were not altered. In all cases, a tolcapone pretreatment decreased homovanillic acid levels and elevated DOPAC levels. In further combination studies, GBR-12909 did not alter significantly the effects of levodopa/carbidopa on dopamine, DOPAC and homovanillic acid levels. In these rats, tolcapone enhanced the effect of GBR-12909 on extracellular dopamine but not on DOPAC. In conclusion, when levodopa and carbidopa are given together, COMT inhibition becomes extremely meaningful, and dopamine levels are multiplied by tolcapone. Otherwise, tolcapone is able to further elevate extracellular dopamine levels only when dopamine 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.

Topics: 3,4-Dihydroxyphenylacetic Acid; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Benzophenones; Carbidopa; Catechol O-Methyltransferase; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Drug Interactions; Enzyme Inhibitors; Extracellular Space; Haloperidol; Homovanillic Acid; Levodopa; Male; Microdialysis; Nitrophenols; Piperazines; Rats; Rats, Wistar; Time Factors; Tolcapone; Visual Cortex