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 tomography (PET), have contributed to the hypothesis that a state of hypometabolism may underlie schizophrenia. The chronic use of methamphetamine (MAP) or phencyclidine (PCP), both of which have been shown to enhance dopaminergic function in the brain, leads to a psychotic state in man which has prompted the suggestion that these compounds may have utility as models of schizophrenia. In the present study, regional alterations in energy metabolism were examined in the rat brain using cytochrome-c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry following chronic treatment with PCP and MAP. PCP and MAP were administered alone or in the presence of fluphenazine or clozapine to animals for 28 days, after which mitochondrial enzyme activities were estimated. Both PCP and MAP produced profoundly similar decreases in COX activity in a broad spectrum of regions. Most prominent in this regard were the caudate-putamen, nucleus accumbens and septum. No changes were noted in sections stained for SDH activity, suggesting that results were dependent upon neither a generalized mitochondrial dysfunction nor mitochondrial loss. Cell counts and TUNEL histochemistry also failed to reveal any significant differences between control and treated animals, implying that reductions were not a result of cell loss. Both clozapine 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.
Prince
J A
JA
Department of Medical Pharmacology, Uppsala University, Sweden.
Yassin
M S
MS
Oreland
L
L
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002452:Cell Count; D003024:Clozapine / Q000494:pharmacology; D003720:Densitometry; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005476:Fluphenazine / Q000494:pharmacology; D006651:Histocytochemistry; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D010622:Phencyclidine; D003024:Clozapine; D005476:Fluphenazine