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Comparison of two new inhibitors of catechol O ‐methylation on striatal dopamine metabolism: a microdialysis study in rats
Author(s) -
Törnwall M.,
Kaakkola S.,
Tuomainen P.,
Kask A.,
Männistö P.T.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13021.x
Subject(s) - microdialysis , dopamine , catechol , catechol o methyl transferase , chemistry , pharmacology , metabolism , neuroscience , biochemistry , medicine , biology , gene , allele
1 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. 2 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%. 3 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. 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 (159% 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 demonstrate that entacapone is a peripheral COMT inhibitor and support the view that CGP 18014 is mainly a centrally acting inhibitor of O ‐methylation.