Modulation of rat brain endogenous dopamine metabolism by new inhibitors of catechol O-methyltransferase.
The extraneuronal and intraneuronal metabolism of rat brain endogenous dopamine was stimulated by amphetamine (5 mg/kg) and pimozide (2 mg/kg), respectively. Additional metabolic effects of two inhibitors of catechol O-methyltransferase (entacapone and tolcapone (both 30 mg/kg)) and a putative central uptake2 inhibitor (CGP 28014 (30 mg/kg)) were assessed. Amphetamine increased striatal dopamine and 3-methoxytyramine and decreased 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The latter two effects were reversed by tolcapone and CGP 28014, but not by entacapone. Tolcapone, CGP 28014 and even entacapone decreased striatal homovanillic acid (HVA) levels. Pimozide-induced striatal DOPAC levels were further increased by tolcapone and CGP 28014. Both substances also decreased striatal HVA levels. Striatal 3-methoxytyramine levels were significantly lowered only by tolcapone. Our results show that enhanced central dopamine metabolism is modified by the inhibition of catechol O-methyltransferase even in the absence of L-3,4-dihydroxyphenylalanine (L-DOPA). The results also suggest that the mechanism of action of CGP 28014 may be other than true inhibition of catechol O-methyltransferase.
Törnwall
M
M
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
Tuomainen
P
P
Männistö
P T
PT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000578:Amidines / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D009596:Nitrophenols; D010868:Pimozide / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077867:Tolcapone
D000578:Amidines; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; D011728:Pyridones; D015102:3,4-Dihydroxyphenylacetic Acid; C067181:N-(2-pyridone-6-yl)-N',N'-di-n-propylformamidine; D010868:Pimozide; C071192:entacapone; D000077867:Tolcapone; D000661:Amphetamine; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid