COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition

Farrell, Sarah; Tunbridge, Elizabeth M.; Braeutigam, Sven; Harrison, Paul J.

doi:10.1016/j.biopsych.2011.12.023

Cited by 133 publications

(141 citation statements)

References 60 publications

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“…Importantly, treatment with the COMT inhibitor tolcapone significantly reversed the Met and Val phenotypes, improving Val/Val mice while reducing alternation in Met/Met mice. These data are similar to the higher performance of Met carriers compared with Val carriers in some working memory tasks in humans (Barnett et al, 2007;Diaz-Asper et al, 2008; but see Barnett et al, 2008), and the reversal of these phenotypes by tolcapone administration Farrell et al, 2012). These data support the hypothesis that there is an 'inverted U-shaped' dose response for catecholamine signaling modulation of cognitive functions such as working memory and/or behavioral flexibility (Bilder et al, 2004;Rolls et al, 2008;Gamo and Arnsten, 2011;Sheynikhovich et al, 2013).…”

Section: Discussionsupporting

confidence: 74%

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Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

Risbrough

Hauger

et al. 2014

Neuropsychopharmacol

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The Val158Met polymorphism of human catechol-o-methyltransferase (COMT) is one of the most well-studied single-nucleotide polymorphisms in neuropsychiatry; however, findings are inconsistent due to human genetic heterogeneity. We created the first 'humanized' COMTVal158Met mouse lines, which carry either human COMT Val or Met alleles via gene targeting. The 'humanized' mouse model enables strict comparison of the physiological functions of the two alleles. Consistent with human observation, Met/Met mice exhibited a 30% reduction in enzymatic activity compared with Val/Val mice. On the basis of the reported differences in human Met and Val carriers across working memory, fear processes and sensorimotor gating, we examined these functions between sibling Met/Met and Val/Val mice. Val/Val mice exhibited robust reductions in spatial working memory compared with Met/Met mice in both sexes, with tolcapone treatment significantly reversing the Val/Val alternation deficits. Sex effects were observed in other behaviors, with male Val/ Val mice exhibited lower prepulse inhibition compared with Met/Met mice, whereas female mice exhibited the opposite phenotype. Female but not male Met/Met mice exhibited reduced contextual fear, increased cued fear, and reduced extinction recall. Thus, these mice (1) support the argument that human COMT Val158Met polymorphism modulates behavioral functions and most importantly (2) exhibit the expected treatment effects supporting the 'inverted U shaped' dose response of catecholamine signaling on cognitive function. This model will be invaluable for understanding the effects of human COMT Val158Met polymorphism on cortical development and behavioral functions, and how this polymorphism modulates treatment response.

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Section: Discussionsupporting

confidence: 74%

“…In humans, working memory has been shown to be associated with the Val158Met polymorphism (eg, Giacoumaki et al, 2008;Farrell et al, 2012). To test working memory, we used a common rodent test of spatial working memory that requires cortical catecholamine signaling (for review see Lalonde, 2002).…”

Section: Working Memory Using T-maze Spontaneous Alternationmentioning

confidence: 99%

Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

Risbrough

Hauger

et al. 2014

Neuropsychopharmacol

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“…Although practice effects are unlikely to confound AMPH effects completely (34), a four-cell study design (placebo/placebo, placebo/drug, drug/placebo, drug/drug) may be needed to separate within-subject practice from drug effects. Although some pharmacological studies have abandoned within-subject designs altogether (in favor of between-subject-only approaches) to guard against potentially problematic practice effects (40,41), withinsubject designs remain a prerequisite for observing drug-related changes in brain activity or performance. The present results show that taking a close look at practice effects in pharmacological imaging research may foster rather than hinder our understanding of DA neuromodulation.…”

Section: Amph-related Relations Between Sd Bold and Wm Performance As Amentioning

confidence: 99%

Amphetamine modulates brain signal variability and working memory in younger and older adults

Garrett

Nagel

Preuschhof

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

106

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Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SD BOLD ) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SD BOLD levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SD BOLD and reaction time means (RT mean ) and SDs (RT SD ). Older adults who received AMPH in the first session tended to improve in RT mean and RT SD when SD BOLD was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD BOLD decreased (for RT mean ) or no effect at all (for RT SD ). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state-and practice-dependent neurochemical basis of human brain dynamics.brain signal variability | dopamine | aging | working memory | fMRI H uman brain signals are characteristically variable and dynamic, at a variety of timescales and levels of analysis (1, 2). For decades, age-related cognitive deficits have been conceptualized as due to various forms of "noisy," inefficient neural processing (3, 4). However, the preponderance of available neuroimaging work on brain signal variability and aging indicates that healthy, higher performing, younger adults typically express more signal variability across trials and time in a variety of cortical regions relative to older, poorer performers (2, 5-7). Theoretical and computational explanations of this finding include notions such as flexibility/adaptability, dynamic range, Bayesian optimality, and multistability (2), but empirically supported mechanisms for age and performance-graded differences in human brain signal dynamics are not yet available. Dopamine (DA) neuromodulation may provide one such mechanism.DA neuromodulation is a leading mechanistic candidate for age-related cognitive losses (8-10). Concurrent with substantia nigra and ventral tegmental DA neuron loss, D 1 and D 2 receptor densities reduce notably from early to late adulthood acro...

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“…37 This explanation is supported by several studies demonstrating that pharmacological interventions that increase levels of extracellular catecholamines result in improved cognitive performance in val homozygotes and impairment in met homozygotes. [38][39][40][41] It is possible that the heightened noradrenergic neuro transmission associated with arousing stimuli shifts met homozygotes to a more disadvantageous functional position with respect to emotional processing. This would be consistent with the functional neuroimaging data reporting increased prefrontal/limbic activation in met relative to val carriers during emotional processing tasks.…”

Section: J Psychiatry Neurosci 2014;39(3)mentioning

confidence: 99%

“…Such gene × drug interactions have already been demonstrated in association with the effects of catecholaminergic agents on cognitive performance. [24][25][26] Here, we hypothesized that the COMT val158met genotype would also moderate the effect of such drugs on emotional processing. We therefore set out to examine the effects of the selective nor adrenaline reuptake inhibitor (NRI) antidepressant reboxetine on emotional processing in healthy volunteers based on COMT genotype.…”

Section: Introductionmentioning

confidence: 99%

Catechol-O-methyltransferase val158met genotype determines effect of reboxetine on emotional memory in healthy male volunteers

Gibbs

Bautista

Mowlem

et al. 2014

J Psychiatry Neurosci

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IntroductionThe catechol-O-methyltransferase (COMT) enzyme is responsible for degradation of catecholamines, such as dopamine (DA) and noradrenaline. The substitution of methionine (met) for valine (val) at codon 158 in the COMT gene is associated with a 40% reduction in enzyme activity and higher levels of extracelluar DA.1 This single nucleotide polymorphism has been most extensively studied in relation to cognitive function; several studies have linked the low-activity met allele to enhanced performance on prefrontal cortex (PFC) tasks compared with the high-activity val allele, albeit with some inconsistencies. 2In addition, there is evidence suggesting COMT involvement in emotional processing. Several studies have demonstrated increased limbic-prefrontal activation in response to negative emotional stimuli in healthy met carriers. [3][4][5][6] This has been taken to represent less efficient emotional processing in met, compared with val, allele carriers. Other studies have found the reverse pattern -increased limbic reactivity in response to emotional stimuli in val, compared with met carriers.7-9 However, a meta-analysis of functional neuroimaging Background: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. Methods: We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the select ive noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. Results: We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimu li that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. Limitations: We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. Conclusion: Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development.

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COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition

Cited by 133 publications

References 60 publications

Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

Amphetamine modulates brain signal variability and working memory in younger and older adults

Catechol-O-methyltransferase val158met genotype determines effect of reboxetine on emotional memory in healthy male volunteers

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