Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats

6-Nitronoradrenaline, a bioactive compound recently identified in the brain , is known to inhibit catechol-O-methyltransferase. To study its effect on dopamine metabolism, it was administered into rat striatum via a microdialy sis probe. Other nitrated catechols (6-nitrodopamine, 6-nitro-DOPAC and 5-n itro-HVA) were studied for comparison. Tolcapone, a selective catechol-O-me thyltransferase inhibitor, was used as a positive reference compound. Both 6-nitronoradrenaline and tolcapone increased striatal extracellular dopamin e levels during the perfusion (at 100 muM concentration but not at 10 muM) and decreased the efflux of homovanillic acid. Tolcapone, but not other nit rated catechols, increased 3,4-dihydroxyphenylacetic acid efflux. None of t he compounds inhibited MAO-B activity at 100 muM or lower. At 1 mM, 6-nitro dopamine inhibited MAO-B by 60%. Compared to tolcapone, other nitrated cate chols were very weak COMT inhibitors in vitro. Neither tolcapone nor 6-nitr onoradrenaline modified the metabolism Of L-dopa which was given peripheral ly. In binding studies, both 6-nitronoradrenaline and other nitrocatechols failed to affect the dopamine transporter even at high mu molar concentrati ons. In conclusion, exogenous 6-nitronoradrenaline can act as a COMT inhibi tor in the striatum and elevate striatal dopamine levels without inhibiting dopamine reuptake. Whether endogenous 6-nitronoradrenaline can be formed a lso in vivo in the striatum and act as a regulator of dopaminergic tone rem ains to be determined (C) 2001 Elsevier Science BN. All rights reserved.