OXIDATIVE REACTIONS AND SCHIZOPHRENIA - A REVIEW-DISCUSSION

Now that definitive direct evidence has been obtained that oxidized me tabolites of catecholamines - aminochrome (derived from dopamine) and related compounds - occur in the human brain the question this paper e xplores is what is their function there, if any. They are precursors o f neuromelanin and are formed inter alia by co-oxidation by prostaglan din H synthase during the synthesis of prostaglandin Il from arachidon ic acid. Their further metabolism by NAHPD-cytochrome P450 reductase f orms the highly neurotoxic o-semiquinone together with free oxygen rad icals. The defenses against these orthoquinones (o-quinones) and o-sem iquinones (which include reduction, O-methylation, 5-cysteinylization, glutathione conjugation, conversion to the o-hydroquinone, and neurom elanin formation), and their possible status in schizophrenia, are rev iewed. This system is closely linked with glutamate neurotoxicity beca use glutamate receptors activate PGH synthase and because dopamine tox icity is mediated by these o-quinones acting on NMDA receptors. Intera ctions between glutamate and dopamine neurotoxicity are explored, incl uding a possible role for the redox properties of catecholamines. The hypothesis is presented that some of the demonstrated cellular damage in the schizophrenic brain may be mediated by catecholamine o-quinones . The significance of the evidence from previous studies carried out 4 0 years ago, that a closely related catecholamine o-quinone - adrenoch rome - has psychotomimetic properties in humans and behavior disruptin g properties in animals, is reviewed in the light of these recent find ings.