title: Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity.
abstract: Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val158Met) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes. Despite robust alterations in dopamine metabolism, we found only subtle changes on certain cognitive tasks under baseline conditions (eg, increased spatial novelty preference in COMT-Met mice vs wild-type mice). However, genotype differences emerged after administration of the COMT inhibitor tolcapone: performance of wild-type mice, but not COMT-Met mice, was improved on the 5-choice serial reaction time task after tolcapone administration. There were no changes in anxiety-related behaviors in the tests that we used. Our findings are convergent with human studies of the Val158Met polymorphism, and suggest that COMT's effects are most prominent when the dopamine system is challenged. Finally, they demonstrate the importance of considering COMT genotype when examining the therapeutic potential of COMT inhibitors.
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Barkus
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: Clio
authors.identifier: 0000-0001-6328-6876
authors.initials: C
authors.lastname: Korn
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stumpenhorst
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Laatikainen
authors.affiliation: Medical School, University of Oxford, Oxford, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Ballard
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Sheena
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Sharp
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.|Oxford Health NHS Foundation Trust, Oxford, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.|Oxford Health NHS Foundation Trust, Oxford, UK.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Tunbridge
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D002755:Choice Behavior / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005838:Genotype; D018782:Maze Learning / Q000187:drug effects; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D000077867:Tolcapone; D014633:Valine / Q000235:genetics
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D008715:Methionine; D000077867:Tolcapone; C000593198:COMT protein, mouse; D002394:Catechol O-Methyltransferase; D014633:Valine