COMPARISON OF 2 NEW INHIBITORS OF CATECHOL O-METHYLATION ON STRIATAL DOPAMINE METABOLISM - A MICRODIALYSIS STUDY IN RATS

1 Effects of two new inhibitors of catechol O-methylation (CGP 28014 a nd entacapone; 30 mg kg(-1), i.p.) were compared by means of brain mic rodialysis in rats treated with L-3,4-dihydroxyphenylalanine (L-dopa)/ carbidopa (50/50 mg kg(-1), i.p., respectively) or saline. 2 In. salin e-treated rats, CGP 28014 maximally (max) increased striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) effluxes by 41% and 49%, re spectively, whereas homovanillic acid (KVA) levels were decreased by 7 1%. 3 In the presence of L-dopa/carbidopa, a peripherally active inhib itor of catechol O-methyltransferase (COMT) entacapone had a short-las ting increasing effect on L-dopa efflux. Compared to the effects of L- dopa/carbidopa alone 3-O-methyldopa (3-OMD) levels were effectively re duced (max 79%) by entacapone, but not by CGP 28014. 4 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 (1 59% at 180 min). 5 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%). 6 Our results demons trate that entacapone is a peripheral COMT inhibitor and support the v iew that CGP 18014 is mainly a centrally acting inhibitor of O-methyla tion.