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.