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

Budygin, Evgeny A.; Gainetdinov, Raul R.; Kilpatrick, Michaux; Rayevsky, K.S.; Männistö, Pekka T.; Wightman, R. Mark

doi:10.1016/s0014-2999(99)00084-9

Cited by 43 publications

(48 citation statements)

References 24 publications

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“…Taken together, GBR 12909 induced only minor changes in dopamine metabolism and there were no indications of potentiation by COMT deficiency on these effects. These results fit quite well with previous findings in rats, where GBR 12909 alone had no effect on DOPAC and HVA striatal extracellular and brain tissue concentrations (Westerink et al, 1987;Irifune et al, 1995;Budygin et al, 1999;Huotari et al, 1999). However, when tolcapone, a selective and potent COMT inhibitor (Borgulya et al, 1989), was given together with 20 mg/kg GBR 12909, striatal extracellular DOPAC levels were slightly increased (Huotari et al, 1999), whereas with 10 mg/kg GBR 12909 DOPAC levels remained unaltered (Budygin et al, 1999).…”

Section: Discussionsupporting

confidence: 91%

“…In previous studies with rats, the selective COMT inhibitor tolcapone was able, to some extent, to potentiate GBR 12909-induced elevation of striatal extracellular dopamine concentration (Budygin et al, 1999;Huotari et al, 1999). In the present study, we have investigated the effects of the dopamine uptake inhibition on locomotor activity, the levels of catecholamines and their metabolites in three different brain regions, and dopamine concentration in striatal extracellular fluid of COMT-deficient mice of both sexes.…”

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confidence: 83%

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Effect of Dopamine Uptake Inhibition on Brain Catecholamine Levels and Locomotion in Catechol-O-methyltransferase-Disrupted Mice

Huotari

Sántha

Lucas

et al. 2002

J Pharmacol Exp Ther

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Two different uptake processes terminate the synaptic action of released catecholamines in brain: the high-affinity uptake to presynaptic nerve terminals (uptake 1 , followed by oxidation by monoamine oxidase, MAO) or glial cells uptake (uptake 2 , followed by O-methylation by catechol-O-methyltransferase, COMT, and/or oxidation by MAO). For dopaminergic neurons, uptake by the high-affinity dopamine transporter (DAT) is the most effective mechanism, and the contribution of glial COMT remains secondary under normal conditions. In the present study we have characterized the role of COMT using COMT-deficient mice in conditions where DAT is inhibited by 1-[2-[bis(4-fluorophenyl)methoxy-]ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12909) or cocaine. In mice lacking COMT, GBR 12909 results in total brain tissue dopamine levels generally higher than in wildtype mice but no such potentiation was ever seen in striatal extracellular fluid. Dopamine accumulation in nerve endings is more evident in striatum and hypothalamus than in cortex. Both GBR 12909 and cocaine induced hyperlocomotion in mice lacking COMT. Unexpectedly, hyperactivity induced by 20 mg/kg GBR 12909 was attenuated only in male COMT knockout mice, i.e., they had an inability to sustain the hyperactivity induced by DAT inhibition. Furthermore, attenuation of hyperlocomotion was observed also after cocaine treatment in both C57BL/6 (at 5 and 15 mg/kg) and 129/Sv (at 30 mg/kg) genetic background COMT-deficient male mice. Despite the possible interaction between DAT and extraneuronal uptake (and subsequently COMT), the role of COMT in dopamine elimination is still minimal in conditions when DAT is inhibited.The dopamine transporter (DAT) and monoamine oxidase (MAO) play key roles in dopamine elimination and are expected to have pleiotropic effects on susceptibility to a wide range of behavioral/psychiatric disorders and symptoms associated with dysregulation of dopamine transmission. Due the extraneuronal location in the brain (astrocytes, capillary walls, and postsynaptic dendritic spines; Karhunen et al., 1995), the significance of catechol-O-methyltransferase (COMT) on dopamine metabolism remains secondary under normal conditions.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 83%

Effect of Dopamine Uptake Inhibition on Brain Catecholamine Levels and Locomotion in Catechol-O-methyltransferase-Disrupted Mice

Huotari

Sántha

Lucas

et al. 2002

J Pharmacol Exp Ther

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“…Our present neurochemical results in COMT-deficient mice with a lower dose (2.5 mg/kg) of d-amphetamine are in line with previous findings that COMT inhibition did not further potentiate d-amphetamine-induced changes in neurochemical or behavioral parameters Tuomainen et al 1996). This contrasts with the results of similar experiments with low doses of GBR 12909, a pure DAT inhibitor (Andersen 1989), where the effects of the drug on dopamine levels were augmented by both a potent COMT inhibitor tolcapone (Budygin et al 1999;Huotari et al 1999) and the lack of COMT (Huotari et al 2002b).…”

Section: Discussionsupporting

confidence: 88%

d -Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice

et al. 2004

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Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D(1) and D(2) receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.

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“…Properly spaced in time, the dopamine release from a mild stimulation train (e.g., bipolar, 24 pulses, 60 Hz, 120 A) is highly reproducible, with minimal effects on behavior. Therefore, electrically evoked dopamine release and uptake can be monitored before and after administration of a drug (1,(51)(52)(53)(54). Background-subtracted cyclic voltammograms in a freely moving male rat (solid lines) were matched to a template of electrically evoked dopamine release in the same rat (dashed lines).…”

Section: Electrically Stimulated Dopamine Releasementioning

confidence: 99%