Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity

Barkus, Christopher; Korn, Clio; Stumpenhorst, Katharina; Laatikainen, L M; Ballard, Dominic; Lee, Sheena; Sharp, Trevor; Harrison, Paul J.; Bannerman, David M.; Weinberger, Daniel R.; Chen, Jingshan; Tunbridge, Elizabeth M.

doi:10.1038/npp.2016.119

Cited by 18 publications

(15 citation statements)

References 55 publications

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“…Because tolcapone appears to be free of major psychostimulant properties and abuse potential [13], the pharmacodynamic profile of this COMT inhibitor may be beneficial to improve vigilance in sleepy patients and healthy individuals undergoing SD. Indeed, previous research consistently concluded that this compound may improve distinct aspects of cognitive functions in Parkinson's patients [36] and in healthy volunteers [10,11,13], as well as in rats and mice [12,37,38]. While we expected that especially individuals with high COMT activity (Val/Val genotype) may benefit from pharmacological COMT inhibition, we found that tolcapone does not improve sustained attention after prolonged wakefulness in any COMT genotype.…”

Section: Discussioncontrasting

confidence: 49%

“…A common valine-tomethionine substitution at codon 158 of COMT protein (Val158-Met single-nucleotide polymorphism (SNP); SNP-Id: rs4680) drastically reduces enzymatic activity [7], leading to elevated PFC dopaminergic tone in Met/Met homozygotes when compared to Val/Val homozygotes [5]. While COMT genotype modulates PFC functioning [5,8], some effects of this polymorphism may only become prominent when the dopamine system is challenged, such as with behavioral or pharmacological interventions including sleep deprivation (SD) [3,9] and administration of the brain penetrant COMT inhibitor tolcapone [10][11][12]. Tolcapone is a nonstimulant drug thought to lead to relatively specific increases in PFC dopamine [10,11,13].…”

Section: Introductionmentioning

confidence: 99%

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Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men

Valomon

Holst

Borrello

et al. 2018

Neuropsychopharmacol

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Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shape relationship, independently of neurophysiological markers of elevated sleep need.

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Section: Discussioncontrasting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men

Valomon

Holst

Borrello

et al. 2018

Neuropsychopharmacol

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“…148 The human COMT gene contains a polymorphism (Val158Met) that alters its enzyme activity and influences prefrontal cortex function, 149, 150 and the Met allele appears to be human specific. 151, 152 Recently, Barkus et al 153 introduced the human Met allele into the native mouse COMT gene to produce COMT -Met mice, and developed a mouse model of altered COMT activity comparing with their wild-type littermates. COMT -Met mice had reductions in COMT abundance and activity compared with wild-type controls.…”

Section: Functional Analyses Of Genetic Risk In Vitro and In Vivomentioning

confidence: 99%

“…When administered with the COMT inhibitor tolcapoe, the attentional performance (assessed with 5-choice serial reaction time task) was only improved in wild-type mice but not in the COMT -Met mice. 153 This genetic mutation knock-in mouse model provided an interesting template to study the functions of human risk variant in animals.…”

Section: Functional Analyses Of Genetic Risk In Vitro and In Vivomentioning

confidence: 99%

Molecular mechanisms underlying noncoding risk variations in psychiatric genetic studies

Xiao

Chang

2017

Mol Psychiatry

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Recent large-scale genetic approaches such as genome-wide association studies have allowed the identification of common genetic variations that contribute to risk architectures of psychiatric disorders. However, most of these susceptibility variants are located in noncoding genomic regions that usually span multiple genes. As a result, pinpointing the precise variant(s) and biological mechanisms accounting for the risk remains challenging. By reviewing recent progresses in genetics, functional genomics and neurobiology of psychiatric disorders, as well as gene expression analyses of brain tissues, here we propose a roadmap to characterize the roles of noncoding risk loci in the pathogenesis of psychiatric illnesses (that is, identifying the underlying molecular mechanisms explaining the genetic risk conferred by those genomic loci, and recognizing putative functional causative variants). This roadmap involves integration of transcriptomic data, epidemiological and bioinformatic methods, as well as in vitro and in vivo experimental approaches. These tools will promote the translation of genetic discoveries to physiological mechanisms, and ultimately guide the development of preventive, therapeutic and prognostic measures for psychiatric disorders.

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“…While there have been a number of studies investigating how DAT and COMT shape reward pursuit and cognitive functions like working memory, respectively (11)(12)(13)(14)(15), their role in regulating behavioral flexibility has been comparatively neglected. Individual variation in DAT or COMT function in humans has been shown to correlate with differences in reinforcement learning and flexible decision making (16)(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility

Korn

Akam

Jensen

et al. 2019

Preprint

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Mechanisms for regulation of dopamine transmission are critical to its effects on behavior and vary by region. Recycling via the dopamine transporter (DAT) predominates in striatum, while degradation by catechol-O-methyltransferase (COMT) predominates in cortex. However, questions remain about whether and how each mechanism affects fast fluctuations in dopamine transmission in these regions and influences behavior. To address this issue, we used pharmacological blockade of each clearance mechanism to assess their roles in reward-guided decision making and in regulating sub-second dopamine transmission in striatum and cortex.We found that DAT and COMT selectively influence reward value updating in opposite directions, with DAT blockade impairing and COMT inhibition improving learning in a multi-step decision making task that requires mice to monitor changes in both optimal response strategy and reward probabilities. By contrast, neither drug influenced the speed of reversals following a change in action-state transition probabilities. In addition, DAT but not COMT influenced task engagement and motivation to work for reward in both the decision making task and a progressive ratio paradigm. Fast scan cyclic voltammetry recordings of evoked dopamine release in anesthetized mice revealed that DAT but not COMT blockade enhanced dopamine transients in nucleus accumbens. Unexpectedly, neither manipulation had an effect on evoked release in medial frontal cortex. Together, these data refine our understanding of how dopamine clearance mechanisms operate in different regions and at distinct timescales to shape aspects of reward-guided decision making. 3 Significance StatementDopamine transmission is tightly regulated by clearance mechanisms and these clearance mechanisms exhibit regional specificity. However, while we know a lot about how the activity of dopamine neurons relates to reward-guided behavior, the precise role of different clearance mechanisms in shaping these processes is much less understood. This is important, as dysfunctional clearance mechanisms have been implicated in many neuropsychiatric disorders.Here, we show specific and distinct roles for two clearance mechanisms -the dopamine transporter and catechol-O-methyltransferase -in reward value, but not action-state probability, updating during multi-step decision making, and in regulating striatal and cortical dopamine transients. Our findings demonstrate how regulation of dopamine transmission, over distinct timescales and in different brain regions, can influence multiple aspects of reward-guided behavior.

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Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity

Cited by 18 publications

References 55 publications

Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men

Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men

Molecular mechanisms underlying noncoding risk variations in psychiatric genetic studies

Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility

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