Effects of tolcapone, a novel catechol- O-methyltransferase inhibitor, on striatal metabolism of L-DOPA and dopamine in rats

Abstract

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 a 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.