Effects of catechol-O-methyltransferase inhibitors and L-3,4-dihydroxyphenylalanine with or without carbidopa on extracellular dopamine in rat striatum.
The effects of two new catechol-O-methyltransferase (COMT) inhibitors, OR-611 and Ro 40-7592, in combination with L-3,4-dihydroxyphenylalanine (L-dopa) with or without carbidopa on extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-O-methyldopa (3-OMD), and 5-hydroxyindoleacetic acid in rat striatum were studied. A dose of 10 mg/kg i.p. of Ro 40-7592 alone, in contrast to the same dose of OR-611, decreased the dialysate level of HVA and increased that of DOPAC; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. L-Dopa (50 mg/kg i.p.) alone slightly increased extracellular levels of DA, DOPAC, and HVA. The effects of L-dopa were potentiated by carbidopa (50 mg/kg i.p.), and even 3-OMD levels in dialysate samples became detectable. Both OR-611 and Ro 40-7592 significantly further increased the DA and DOPAC efflux from striatum produced by L-dopa. This increase was more pronounced when carbidopa was added to the treatment. OR-611 did not modify the effect of L-dopa or carbidopa/L-dopa on dialysate HVA levels, whereas Ro 40-7592 markedly reduced those levels. Both OR-611 and Ro 40-7592 very clearly suppressed dialysate 3-OMD levels produced by carbidopa/L-dopa. Ro 40-7592 was more effective than OR-611 in potentiating the effects of L-dopa or carbidopa/L-dopa. These in vivo data show that the new COMT inhibitors markedly inhibit the O-methylation of L-dopa and increase its availability to brain, which is reflected as increased DA formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Kaakkola
S
S
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
Wurtman
R J
RJ
D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D008297:Male; D009570:Nitriles; D009596:Nitrophenols; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077867:Tolcapone; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; D014443:Tyrosine; C071192:entacapone; D004295:Dihydroxyphenylalanine; D000077867:Tolcapone; D002230:Carbidopa; C008404:3-methoxytyrosine; D004298:Dopamine