Many of the hypotheses of the cause of schizophrenia have involved abnormalities of methyl carbon metabolism; this proposal is designed to examine the role of the methyl carbon in schizophrenia and other psychoses. While dopaminergic systems are clearly involved in both schizophrenia and affective disorders, there is as yet no clear indication of a specific biochemical defect by which the genetic determinants are expressed. Based on previous work in our laboratory which indicates an abnormality in the methyl carbon pathway, this project has been designed to determine the site of abnormal methyl carbon oxidation in psychosis by administering specific 14C-labelled pathway intermediates to patients in vivo. A defect in methyl metabolism could affect dopaminergic function by a number of mechanisms, such as a consequent inability of catechol-O-methyl transferase to inactivate dopamine or disturbance of receptors via a defect in membrane phospholipid methylation. It could also be the resultant effect of diversion of methyl groups to methylate an expanded pool of metabolites requiring methylation. Demonstration of a causative defect in psychoses would enable design of more effective therapeutic interventions to alleviate these chronic debilitating diseases. By administering radiolabelled metabolic intermediates to unmedicated patients under dietary control and measuring the expired 14CO2 and the rate of appearance of 14C in metabolites in plasma, a determination will be made as to the integrity of different metabolic steps in the methyl carbon pathway. If one or more specific metabolic defects are demonstrated in patients with schizophrenia, patients with affective disorders will be studied at the end of the project to examine the possibility of a unitary cause of psychosis, or of different methyl metabolism errors. Examination of the pathways will be studied in animals using labelled precursors, after pretreating the animals with selected inhibitors and loading doses of metabolites; 14C in CO2 and metabolites in plasma and in organs will be measured. HPLC separations have been developed for pathway intermediates, and a new Accelerator Mass Spectrometry (AMS) method will be used for high sensitivity 14C counting. The data from the above observations will be used to formulate an appropriate kinetic model that describes the methyl carbon pathway, and to determine the range of rate constants associated with psychosis.
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