tolcapone and 3-methoxytyramine

In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-dopa (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in dose-dependent increase of dialysate levels of L-dopa and 3-O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-dopa, markedly enhanced the elevation or extracellular L-dopa, while it completely prevented the formation of 3-O-methyl-DOPA. In another experiment, the administration of L-dopa + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-dopa bioavailability through peripheral and central inhibition of L-dopa O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benserazide; Benzophenones; Catechol O-Methyltransferase Inhibitors; Chromatography, High Pressure Liquid; Dopamine; Dose-Response Relationship, Drug; Extracellular Space; Homovanillic Acid; Levodopa; Male; Methylation; Microdialysis; Neostriatum; Nitrophenols; Rats; Tolcapone

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.

Topics: 3,4-Dihydroxyphenylacetic Acid; Amidines; Amphetamine; Animals; Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Corpus Striatum; Dopamine; Homovanillic Acid; Male; Neurons; Nitriles; Nitrophenols; Pimozide; Pyridones; Rats; Rats, Wistar; Tolcapone