Antipsychotic drugs (APDs) are used to treat schizophrenia and they have the potential to ameliorate the clinical symptoms. Because APDs do take time to exhibit their full therapeutic potential, it has been suggested that molecular changes, i.e. altered gene and protein expression, are an important element of their mechanism of action. These findings and hypotheses imply that (a) treatment with APDs reinstates a process or anatomic substrate that is disturbed in schizophrenia, and (b) that gene expression changes are involved in the reinstatement. An analysis of gene expression changes in the relevant anatomical structures after treatment with APDs could therefore provide valuable information about the disease, the mechanism of action of both conventional and atypical APDs, and it could provide leads in the search for novel treatment strategies. High amongst the relevant anatomical substrates in schizophrenia are limbic structures, particularly the hippocampus and the amygdala. It has been shown consistently that schizophrenia is accompanied by reductions in the hippocampus-amygdala complex. This reduction is correlated with poorer information processing in the disorder. The abnormalities have also been observed in drug-naive patients, indicating that they are not caused by the treatment. The present proposal will investigate gene expression patterns in the hippocampus and the amygdala of rats after chronic treatment with the APDs, haloperidol and clozapine. Both drugs will be used at three different concentrations in independent groups of rats, and analyzed in a manner to further our understanding of the molecular properties that unite these drugs, as well as properties that separate them. Furthermore, we will establish a gene expression profile in both anatomic structures that has predictive value for APD exposure. This profile can serve as an assay for future drug-discovery purposes. Relevance: Using recently developed, powerful molecular tools, we propose to investigate how APDs act in brain areas that are altered in schizophrenia. The information gained can be used to (a) understand some of the underlying pathophysiology in schizophrenia, (b) develop more useful assays to scan novel drugs for antipsychotic properties, and (c) develop novel approaches to the treatment of schizophrenia. ? ?
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