The COMT inhibitor tolcapone potentiates the anticataleptic effect of Madopar in MPP(+)-lesioned mice.
Orally administered Madopar (levodopa/benserazide 4:1) dose-dependently antagonized haloperidol-induced (1 mg/kg s.c.) catalepsy in MPP(+)-lesioned mice. Pretreatment with a new selective catechol-O-methyltransferase (COMT) inhibitor, tolcapone (30 mg/kg p.o.), slightly potentiated the antagonistic effect of Madopar (15 mg/kg p.o.) on haloperidol-induced catalepsy. The ability of tolcapone to increase the Madopar effect was significantly attenuated by high doses of 3-O-methyldopa (3-OMD) (800 mg/kg i.p.). This might suggest a competitive blockade of the active transport of levodopa through the blood-brain barrier. In conclusion, the inhibitory effect of tolcapone on the O-methylation of levodopa to 3-OMD by COMT is largely due to improved levodopa and dopamine availability in the brain, and to the reduced formation of 3-OMD.
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
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Himori
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Mishima
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001545:Benserazide / Q000494:pharmacology / Q000627:therapeutic use*; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use*; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy*; D065098:Catechol O-Methyltransferase Inhibitors; D004338:Drug Combinations; D004357:Drug Synergism; D006220:Haloperidol / Q000037:antagonists & inhibitors; D007700:Kinetics; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009596:Nitrophenols; D000077867:Tolcapone; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004338:Drug Combinations; D009596:Nitrophenols; C005177:benserazide, levodopa drug combination; D014443:Tyrosine; D007980:Levodopa; D001545:Benserazide; D000077867:Tolcapone; D006220:Haloperidol; D015655:1-Methyl-4-phenylpyridinium; C008404:3-methoxytyrosine