ANTIPSYCHOTIC DRUG ACTION AFTER HIPPOCAMPAL DAMAGE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: Deformations and functional alterations of the hippocampus, a brain regions important in learning and memory, have been reported in disorders, such as schizophrenia and Alzheimer?s disease, that are commonly treated with antipsychotic drugs. However, it is unknown whether antipsychotic drugs can ameliorate the behavioral consequence of hippocampal dysfunction, or conversely, if hippocampal damage can undermine the behavioral and molecular pharmacology of antipsychotic drugs. The purpose of this grant is to address these issues by using a rat model of excitotoxic hippocampal damage. Methods: The first aim of the grant has been to determine if and how acute or chronic antipsychotic drug treatment can reverse or reduce the effects of hippocampal damage on locomotor activity and spatial working memory. The second aim of the grant has been to determine if the effects of antipsychotic drug treatment on global gene expression are altered by hippocampal damage. The third aim has been to determine if and how hippocampal lesions alter the induction of transcription factors and other proteins by antipsychotic drug treatment. Results: Between July 2005 and February 2006, we have focused our research on two proteins that serve as receptors for antipsychotic drugs, the histamine3 (H3) and alpha2 (?2) adrenergic receptors. Our studies have found that antagonists for the former receptor can moderately improve spatial memory in rats with hippocampal damage, while agonists for the latter site do not improve spatial memory in such animals. These data served as the basis for an R15 application submitted in 2005 by the P.I.. (The application received a score of 199 and was not funded). We have also characterized the effects of hippocampal lesions on global gene expression in the prefrontal cortex using microarray technology. A number of genes related to synaptic function were found to be altered in the prefrontal cortex of lesioned animals. We will continue these lines of research as well as study the effects of antipsychotic drugs on gene and protein expression in the frontal cortex and other brain regions.