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

doi:10.1016/0006-8993(92)91003-W

Brain Research

Volume 587, Issue 2, 7 August 1992, Pages 241-249

https://doi.org/10.1016/0006-8993(92)91003-W Get rights and content

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.

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^∗: Present address: Department of Neurology, University of Helsinki, SF-00290 Helsinki, Finland.

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Research reportEffects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study

Abstract

J. Biol. Chem.

Neuroscience

Eur. J. Pharmacol.

Biochem. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Brain Res.

Trends Pharmacol. Sci.

Life Sci.

Gene

Biochem. Pharmacol.

Neurochem. Int.

Pharmacol. Ther.

Life Sci.

Eur. J. Pharmacol.

O-Methylation of epinephrine and other catechols in vitro and in vivo

Science

Guinea pig striatum as a model of human dopamine deamination: the role of monoamine oxidase isozyme ratio, localization, and affinity for substrate in synaptic dopamine metabolism

J. Neurochem.

cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties

Synthesis of some novel potent and selective catechol-O-methyltransferase inhibitors

J. Med. Chem.

Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form

Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: synthesis and structure-activity studies

Helv. Chim. Acta

Effects of selective monoamine oxidase inhibitors on the in vivo release and metabolism of dopamine in the rat striatum

J. Neurochem.

The presence of the type A form of monoamine oxidase within nigrostriatal dopamine-containing neurons

J. Pharmacol. Exp. Ther.

Dopamine release in rat striatum: physiological coupling to tyrosine supply

J. Neurochem.

Computerized rotometer apparatus for recording circling behavior

Methods Find. Exp. Clin. Pharmacol.

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