Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study

Abstract

In vivo microdialysis was used to examine the effect of two new catechol- O-methyltransferase (COMT) inhibitors, Ro 40-7592 and OR-611, on extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in rat striatum. The interactions of the COMT inhibitors with nomifensine, clorgyline and deprenyl were also studied. Ro 40-7592 (3–30 mg/kg. i.p.) decreased dose-dependently the efflux of HVA, increased that of DOPAC, and tended to increase that of dopamine. Higher doses of OR-611 (30–100mg/kg, i.p.) also decreased the dialysate level of HVA, increased that of DOPAC, and tended to increase that of dopamine. Ro 40-7592 was about ten-fold as potent as OR-611. Neither of the COMT inhibitors changed dialysate levels of 5-HIAA. An OR-611 dose of 10 mg/kg i.p. had no significant effect, in contrast to Ro 40-7592, on any of the parameters studied; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. Both nomifensine (15 mg/kg. i.p.) and clorgyline (4/mg/kg, i.p.) alone elevated extracellular dopamine levels, and lowered those of DOPAC and HVA, though there were quantitative and temporal differences between the drugs. l-Deprenyl (1 mg/kg, i.p.) alone had no significant effect on any of the compounds measured. Ro 40-7592 (10 mg/kg, i.p.) potentiated the effect of nomifensine on dopamine efflux, and it tended to increase clorgy line-induced dopamine efflux, DOPAC levels in dialysates were significantly increased by combinations of Ro 40-7592 and nomifensine or clorgyline, whereas HVA levels remained about as low as they were after Ro 40-7592 had no significant interactions with l-deprenyl. OR-611 (10 mg/kg, i.p.) did not modify the effects on dopamine metabolism of nomifensine, clorgyline or l-deprenyl. These data show that Ro 40-7592 is a potent centrally active COMT inhibitor, whereas OR-611 is principally a peripherally active inhibitor. Use of drugs which inhibit brain COMT can considerable modify dopamine metabolism. COMT inhibitors may be of clinical significance in treating Parkinson's disease.