No change of brain extracellular catecholamine levels after acute catechol-O-methyltransferase inhibition: a microdialysis study in anaesthetized rats

Li, Yinghua; Wirth, Thomas; Huotari, Marko; Laitinen, Kirsti; MacDonald, Ewen; Männistö, Pekka T.

doi:10.1016/s0014-2999(98)00524-x

Cited by 30 publications

(21 citation statements)

References 43 publications

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“…Tolcapone's beneficial effects on PPI and working memory in Val158 homozygotes were not accompanied by changes in activation and mood, suggesting that tolcapone was devoid of gross effects on the mesolimbic and mesostriatal dopaminergic systems in this group. This is consistent with evidence showing that COMT does not significantly affect extracellular DA levels in the rat striatum (Gogos et al, 1998;Li et al, 1998;Mazei et al, 2002;Tunbridge et al, 2004) and suggests that tolcapone's beneficial effects on PPI and cognition would be expected to occur in the absence of psychostimulant effects and abuse potential. The COMT enzyme of Val158 homozygotes may have more capacity to bind tolcapone because of its greater stability (Chen et al, 2004).…”

Section: Discussionsupporting

confidence: 89%

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Giakoumaki

Roussos

Bitsios

2008

Neuropsychopharmacol

129

105

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Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and working memory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the COMT Val158Met polymorphism. Twelve Val/Val and eleven Met/Met healthy male subjects entered the study. Tolcapone 200 mg was administered in two weekly sessions, according to a balanced, crossover, double-blind, placebo-controlled design. PPI was assessed with 5 dB and 15 dB above background prepulses, at 30-, 60-, and 120 ms prepulse-pulse intervals. Subjects also underwent the n-back and the letter-number sequencing (LNS) tasks. PPI was lower in the Val/Val compared to the Met/Met group in the placebo condition. Tolcapone increased PPI significantly in the Val/Val group and tended to have the opposite effect in the Met/Met group. Baseline startle was not affected by tolcapone in the Val/Val group but it was slightly increased in the Met/Met group. Tolcapone improved performance in the n-back and LNS tasks only in the Val/Val group. Enhancement of PFC DA signaling with tolcapone improves both PPI and working memory in a COMT Val158Met genotype-specific manner. These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function. Neuropsychopharmacology (2008) 33, 3058-3068; doi:10.1038/npp.2008 published online 4 June 2008 Keywords: prepulse inhibition; sensorimotor gating; prefrontal cortex; dopamine; cognition; working memory INTRODUCTIONThe enzyme catechol-O-methyltransferase (COMT) is the main catabolic pathway by which dopamine (DA) is removed from the cortical synaptic cleft in humans (Karoum et al, 1994). Indeed, COMT is found in high concentrations in the cortex relative to subcortical regions (Matsumoto et al, 2003) consistent with the absence of functional DA transporters in cortical areas such as the prefrontal cortex (PFC) and hippocampus (Mazei et al, 2002). The Val158Met polymorphism in the COMT gene leads to an amino-acid substitution (valine (Val) to methionine (Met)) and results in the Met/Met variant showing 40% less enzymatic activity than the Val/Val (Chen et al, 2004). There is now abundant evidence (reviewed in Harrison and Weinberger, 2005;Tunbridge et al, 2006) that Met158 allele loading is dose dependently associated with superior performance on a variety of cognitive tests assessing executive function, as well as prefrontal physiology as assessed by neuroimaging. The evidence suggests that PFC DA facilitates 'focusing and stabilizing' activity in PFC networks during executive cognition, ie enhances prefrontal physiologic 'efficiency' by reduction of prefrontal noise (Cools et al, 2002;Mattay et al, 2002Mattay et al, , 2003.Prepulse inhibition (PPI) is thought...

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Section: Discussionsupporting

confidence: 89%

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Giakoumaki

Roussos

Bitsios

2008

Neuropsychopharmacol

129

105

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“…This indicates that inhibition of COMT does not necessarily lead to an enhanced release of dopamine, despite increased levels of dopamine in the neuronal compartment. This is in agreement with results of previous studies with both tolcapone and entacapone while using different experimental approaches [21,22]. In another study [20], while employing a protocol similar to that used here, it was shown that administration of L-DOPA after tolcapone (30 mg/kg) resulted in a significant increase in dopamine levels in striatal dialysates.…”

Section: Discussionsupporting

confidence: 92%

BIA 3-202, a Novel Catechol-O-Methyltransferase Inhibitor, Reduces the Peripheral O-Methylation of <i>L</i>-DOPA and Enhances Its Availability to the Brain

Parada

Soares-da-Silva²

2003

Pharmacology

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The present study aimes at determining the effects of the catechol-O-methyltransferase (COMT) inhibitor BIA 3-202 [1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone] upon levels of L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in peripheral circulation (jugular vein), whole brain, and striatal microdialysates in rats orally treated with L-DOPA plus benserazide. A low dose (3 mg/kg) of BIA 3-202 was relatively selective to inhibit liver COMT, being devoid of major significant inhibitory effects upon brain COMT. By contrast, a high dose (30 mg/kg) of BIA 3-202 markedly inhibited liver and brain COMT. BIA 3-202 (3 and 30 mg/kg) reduced the L-DOPA-induced rise of 3-O-methyl-L-DOPA in the peripheral circulation (jugular vein), brain tissue, and striatal dialysate, but failed to increase the levels of dopamine in striatal dialysates despite the increase in dopamine brain levels. However, the changes in brain levels of L-DOPA, 3-O-methyl-L-DOPA, and dopamine and in striatal dialysate levels of L-DOPA and 3-O-methyl-L-DOPA, obtained with 3 mg/kg BIA 3-202, were not different from those obtained with 30 mg/kg BIA 3-202. In conclusion, inhibition of peripheral COMT by BIA 3-202 may suffice to improve the availability of L-DOPA to the brain.

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“…Previous studies with mice deficient in COMT (Gogos et al, 1998;Huotari et al, 2002), MAO-A (Cases et al, 1995), MAO-B (Chen et al, 1999), and DAT (Giros et al, 1996), as well as a series of studies using MAO-A and -B (Butcher et al, 1990;Kaakkola and Wurtman, 1992) and COMT inhibitors (Kaakkola and Wurtman, 1992;Li et al, 1998) suggest that 1) for dopaminergic neurons, uptake by the DAT is the most effective mechanism for terminating the synaptic actions of dopamine; 2) dopamine oxidation is a preferable metabolic route to methylation; and 3) dopamine levels are generally refractory to changes in activity of both MAO and COMT. The contribution of glial COMT remains, therefore, secondary under normal conditions at least in the striatal regions.…”

Section: Discussionmentioning

confidence: 99%

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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No change of brain extracellular catecholamine levels after acute catechol-O-methyltransferase inhibition: a microdialysis study in anaesthetized rats

Cited by 30 publications

References 43 publications

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

BIA 3-202, a Novel Catechol-O-Methyltransferase Inhibitor, Reduces the Peripheral O-Methylation of <i>L</i>-DOPA and Enhances Its Availability to the Brain

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

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