ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2014
Generation and characterization of humanized mice carrying COMT158 Met/Val alleles.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Trial
- The therapeutic potential of COMT inhibition: cognition and beyond.Molecular psychiatry · 2026Review
- Decoding the bidirectional links between alcohol misuse and aggression: toward a unified translational framework.Psychopharmacology · 2026Review
- DNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans.Molecular psychiatry · 2024Article
- Catechol-O-Methyltransferase Effects on Smoking: A Review and Proof of Concept of Sex-Sensitive Effects.Current behavioral neuroscience reports · 2022Article
- Article
- Chronic presence of blood circulating anti-NMDAR1 autoantibodies impairs cognitive function in mice.PloS one · 2021Article
- Article
- Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility.Psychopharmacology · 2020Article
- Effort-related decision making in humanized COMT mice: Effects of ValPharmacology, biochemistry, and behavior · 2020Article
- Pharmacological studies of effort-related decision making using mouse touchscreen procedures: effects of dopamine antagonism do not resemble reinforcer devaluation by removal of food restriction.Psychopharmacology · 2020Article
- Systems pharmacogenomics - gene, disease, drug and placebo interactions: a case study in COMT.Pharmacogenomics · 2019Article
- Heritable Differences in Catecholamine Signaling Modulate Susceptibility to Trauma and Response to Methylphenidate Treatment: Relevance for PTSD.Frontiers in behavioral neuroscience · 2019Article
- Differential COMT expression and behavioral effects of COMT inhibition in male and female Wistar and alcohol preferring rats.Alcohol (Fayetteville, N.Y.) · 2018Article
- Individual variation in working memory is associated with fear extinction performance.Behaviour research and therapy · 2018Article
- Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits.Molecular psychiatry · 2018Article
- Synaptic Effects of Dopamine Breakdown and Their Relation to Schizophrenia-Linked Working Memory Deficits.Frontiers in synaptic neuroscience · 2018Article
- Gambling disorder: an integrative review of animal and human studies.Annals of the New York Academy of Sciences · 2017Review
- Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2016Article
- Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice.Behavioural pharmacology · 2016Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.