Comparison of two new inhibitors of catechol O‐methylation on striatal dopamine metabolism: a microdialysis study in rats

Abstract

Effects of two new inhibitors of catechol O‐methylation (CGP 28014 and entacapone; 30 mg kg−1, i.p.) were compared by means of brain microdialysis in rats treated with l‐3,4‐dihydroxyphenylalanine (l‐dopa)/carbidopa (50/50 mg kg−1, i.p., respectively) or saline. In saline‐treated rats, CGP 28014 maximally (max) increased striatal dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) effluxes by 41% and 49%, respectively, whereas homovanillic acid (HVA) levels were decreased by 71%. In the presence of l‐dopa/carbidopa, a peripherally active inhibitor of catechol O‐methyltransferase (COMT) entacapone had a short‐lasting increasing effect on l‐dopa efflux. Compared to the effects of l‐dopa/carbidopa alone 3‐O‐methyldopa (3‐OMD) levels were effectively reduced (max 79%) by entacapone, but not by CGP 28014. Entacapone, in contrast to CGP 28014, increased striatal dopamine efflux (max 492% of that after l‐dopa/carbidopa alone). Also DOPAC levels were increased by entacapone (255% at 180 min), but not significantly by CGP 28014 (159% at 180 min). Both compounds initially decreased HVA efflux. The effect of CGP 18014 was longer‐lasting. By the end of the measurement, entacapone even increased HVA levels (max 259%). Our results demonstrate that entacapone is a peripheral COMT inhibitor and support the view that CGP 18014 is mainly a centrally acting inhibitor of O‐methylation. 1994 British Pharmacological Society