Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice.
Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes.
Huotari
Marko
M
University of Kuopio, Department of Pharmacology and Toxicology, PO Box 1627, FIN-70211 Kuopio, Finland. Marko.Huotari@uku.fi
Gogos
Joseph A
JA
Karayiorgou
Maria
M
Koponen
Olli
O
Forsberg
Markus
M
Raasmaja
Atso
A
Hyttinen
Juha
J
Männistö
Pekka T
PT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D002230:Carbidopa / Q000493:pharmacokinetics; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D003342:Corpus Striatum / Q000201:enzymology*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000493:pharmacokinetics; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000493:pharmacokinetics; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000378:metabolism; D008750:Methyldopa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism
D015259:Dopamine Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D008734:Methoxyhydroxyphenylglycol; D008750:Methyldopa; D002394:Catechol O-Methyltransferase; D002230:Carbidopa; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid