NORMALIZATION OF CYTOCHROME-C-OXIDASE ACTIVITY IN THE RAT-BRAIN BY NEUROLEPTICS AFTER CHRONIC TREATMENT WITH PCP OR METHAMPHETAMINE

Previous studies, primarily involving the use of positron emission tom ography (PET), have contributed to the hypothesis that a state of hypo metabolism may underlie schizophrenia. The chronic use of methamphetam ine (MAP) or phencyclidine (PCP), both of which have been shown to enh ance dopaminergic function in the brain, leads to a psychotic state in man which has prompted the suggestion that these compounds may have u tility as models of schizophrenia In the present study, regional alter ations in energy metabolism were examined in the rat brain using cytoc hrome-c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry following chronic treatment with PCP and MAP. PCP and MAP were admini stered alone or in the presence of fluphenazine or clozapine to animal s for 28 days, after which mitochondrial enzyme activities were estima ted. Both PCP and MAP produced profoundly similar decreases in COX act ivity in a broad spectrum of regions. Most prominent in this regard we re the caudate-putamen, nucleus accumbens and septum. No changes were noted in sections stained for SDH activity, suggesting that results we re dependent upon neither a generalized mitochondrial dysfunction nor mitochondrial loss. Cell counts and TUNEL histochemistry also failed t o reveal any significant differences between control and treated anima ls, implying that reductions were not a result of cell loss. Both cloz apine and fluphenazine offered varying degrees of protection from the effects of PCP and MAP. The results provide evidence which implicates dopaminergic hyperactivity in the finding of reduced energy metabolism in the brains of schizophrenics. (C) 1998 Elsevier Science Ltd. All r ights reserved.