Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior
Joseph A. Gogos,Maria A. Morgan,Victoria N. Luine,Miklós Sántha,Sonoko Ogawa,Donald W. Pfaff,Maria Karayiorgou +6 more
TLDR
The results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for comT in some aspects of emotional and social behavior in mice.Abstract:
Catechol-O-methyltransferase (COMT) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines and is considered a candidate for several psychiatric disorders and symptoms, including the psychopathology associated with the 22q11 microdeletion syndrome. By means of homologous recombination in embryonic stem cells, a strain of mice in which the gene encoding the COMT enzyme has been disrupted was produced. The basal concentrations of brain catecholamines were measured in the striatum, frontal cortex, and hypothalamus of adult male and female mutants. Locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior also were analyzed. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. In addition, homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Our results provide conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggest a role for COMT in some aspects of emotional and social behavior in mice.read more
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Parkinson's disease: Mechanisms and models
TL;DR: PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
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Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.
Michael F. Egan,Terry E. Goldberg,Bhaskar Kolachana,Joseph H. Callicott,C.M. Mazzanti,Richard E. Straub,David Goldman,Daniel R. Weinberger +7 more
TL;DR: The data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
Journal ArticleDOI
Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.
TL;DR: This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry.
Journal ArticleDOI
The Hippocampal-VTA Loop: Controlling the Entry of Information into Long-Term Memory
John E. Lisman,Anthony A. Grace +1 more
TL;DR: The concept that the hippocampus and the midbrain dopaminergic neurons of the ventral tegmental area (VTA) form a functional loop is developed and support a model whereby the hippocampal-VTA loop regulates the entry of information into long-term memory.
Journal ArticleDOI
Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain
Jingshan Chen,Barbara K. Lipska,Nader D. Halim,Quang D. Ma,Mitsuyuki Matsumoto,Samer Melhem,Bhaskar Kolachana,Thomas M. Hyde,Mary M. Herman,Jose A. Apud,Michael F. Egan,Joel E. Kleinman,Daniel R. Weinberger +12 more
TL;DR: Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
References
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Book
The Mouse Brain in Stereotaxic Coordinates
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Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders.
Herbert M. Lachman,Demitri F. Papolos,Takuya Saito,Yue Min Yu,Carol L. Szumlanski,Richard M. Weinshilboum +5 more
TL;DR: The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur.
Journal ArticleDOI
Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines
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Journal ArticleDOI
Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA
Olivier Cases,Isabelle Seif,Joseph Grimsby,Patricia Gaspar,Kevin Chen,Sandrine Pournin,Ulrike Müller,Michel Aguet,Charles Babinet,Jean C. Shih,Edward De Maeyer +10 more
TL;DR: Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine, and adults manifested a distinct behavioral syndrome, including enhanced aggression in males.