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The Journal of Neuroscience, March 15, 2003, 23(6):2008
BRIEF COMMUNICATION
Catechol-O-Methyltransferase Genotype and Dopamine
Regulation in the Human Brain
Mayada
Akil,
Bhaskar S.
Kolachana,
Debora A.
Rothmond,
Thomas M.
Hyde,
Daniel R.
Weinberger, and
Joel E.
Kleinman
Clinical Brain Disorders Branch, Intramural Research Program,
National Institute of Mental Health, National Institutes of Health,
Bethesda, Maryland 20892
A functional polymorphism in the gene for
catechol-O-methyltransferase (COMT) has been
shown to affect executive cognition and the physiology of the
prefrontal cortex in humans, probably by affecting prefrontal dopamine
signaling. The COMT valine allele, associated with
relatively poor prefrontal function, is also a gene that may increase
risk for schizophrenia. Although poor performance on executive
cognitive tasks and abnormal prefrontal function are characteristics of
schizophrenia, so is psychosis, which has been related to excessive
presynaptic dopamine activity in the striatum. Studies in animals have
shown that diminished prefrontal dopamine neurotransmission leads to
upregulation of striatal dopamine activity. We measured tyrosine
hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain
and found that the COMT valine allele is also associated with increased
TH gene expression, especially in neuronal populations that project to
the striatum. This indicates that COMT genotype is a heritable aspect
of dopamine regulation and it further explicates the mechanism by which
the COMT valine allele increases susceptibility for psychosis.
Key words:
catechol-O-methyltransferase; dopamine; tyrosine hydroxylase; human; genotype; midbrain; psychosis; schizophrenia
Copyright © 2003 Society for Neuroscience 0270-6474/03/2362008-06$05.00/0
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