Catechol-O-methyltransferase genotype and dopamine regulation in the human brain.
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.
Akil
Mayada
M
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. akilm@intra.nimh.nih.gov
Kolachana
Bhaskar S
BS
Rothmond
Debora A
DA
Hyde
Thomas M
TM
Weinberger
Daniel R
DR
Kleinman
Joel E
JE
D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D001345:Autoradiography; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D021983:Cyclophilins / Q000096:biosynthesis / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012016:Reference Values; D012559:Schizophrenia / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase; D002394:Catechol O-Methyltransferase; D021983:Cyclophilins; D004298:Dopamine