Recent data, obtained by magnetic resonance imaging (MRI), positron emission tomography (PET), electrophysiological methods, and post-mortem examination, suggest that there may be an abnormality in the anterior hippocampal region (including amygdala) in schizophrenia. Hippocampal involvement in schizophrenia is supported by findings indicating that lesions in or stimulation of the hippocampal region can cause symptoms typical of schizophrenia. There is evidence that antipsychotic agents, such as remoxipride and clozapine, may act upon the mesolimbic dopamine system and this lends support to the notion that a functional hippocampal defect in patients with schizophrenia may be a causative factor in the typical symptoms of schizophrenia. Also, myelination of cortico-hippocampal relays occurs during late adolescence, generally the earliest time of onset of psychotic symptoms in patients with schizophrenia. Prefrontal decrease in regional cerebral metabolic rate of glucose (rCMRglc) measured by PET has been noted in some studies of chronic, medication-free patients. This could be related to a defect in the hippocampal region. This project will use the high-resolution (2.6 mm) 600-crystal PET (PET-600) and the tracer [F-18]-2-fluoro-2-deoxyglucose (FDG) for the measurement of rCMRglc in schizophrenia. We will correlate rCMRglc in the hippocampal region with typical symptoms of schizophrenia, in order to test the hypothesis that the hippocampal function is involved in producing these symptoms. We will also study the effects of two different anti-psychotic agents, remoxipride and haloperidol, on hippocampal, limbic, and striatal glucose metabolism in schizophrenia. An important strength of the proposed research is the use of a PET system with sufficient spatial resolution to quantitate activity in the hippocampal region. Blurring (lower recovery coefficients) seen in lower resolution systems results in a reduction of the apparent metabolic rate. High resolution of the scanner, however, increases the need for accuracy of positioning. We achieve this accuracy by the use of high resolution emission and transmission images obtained with the same instrument, as well as with magnetic resonance imaging (MRI). A total of 24 normal subjects and 24 patients with schizophrenia will be studied over a 4 year period. Twelve of the patients will be studied after a two week medication-free period and again after six weeks of treatment with remoxipride. The remaining twelve patients will be studied after two weeks free of medication and again after six weeks of treatment with haloperidol. This project is focused on the investigation of hippocampal metabolism in schizophrenia seeking to localize functional abnormalities. The relationship between anterior hippocampal region (including amygdala) and striatal region rCMRglc with psychotic and motor symptoms of schizophrenia will be studied.
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