Antipsychotic effects on N-acetyl aspartate in rat brain

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Antipsychotic medications primarily have been used to treat schizophrenia, although they are used increasingly to treat other psychiatric illnesses as well. The mechanisms by which these medications act are not well understood, nor are there good predictors of therapeutic response. To address this gap in knowledge, we are applying magnetic resonance spectroscopy (MRS) as a tool for investigating and monitoring the effects of antipsychotics. Our goal is to separate the effects of antipsychotic medications on the MRS signal from the effects of disease, which will provide the foundation for using MRS to monitor and predict patient response to antipsychotics. We hypothesize that, compared with controls, the tissue concentrations of NAA in rat brain decrease progressively during long-term treatment with high doses of the typical antipsychotic haloperidol and the atypical antipsychotic clozapine, but not low doses, and that the decrease will be greater for haloperidol. The specific aim of this proposal is to quantify the NAA tissue concentrations in normal rat brain before and during administration of two dose levels of haloperidol, clozapine, or control solution. We are primarily interested in NAA, which is a biomarker of neuronal health that is altered in schizophrenia. The effects of antipsychotic treatment on MRS measures of NAA are unclear. Several MRS studies indicate that NAA levels decrease following antipsychotic treatment. However, other studies have reported no effects on NAA after treatment. Our preliminary results using MRS in rat brain indicate that no short-term changes occur in NAA levels following low doses of antipsychotics. Neither the dose- nor time dependency of MRS measures of NAA levels following antipsychotic administration have been examined systematically. We plan to address this issue and test our hypothesis by extending our preliminary findings. We will acquire MRS data monthly from the brains of rats that receive one of two doses of haloperidol, clozapine, or control solution daily for six months. We will calculate NAA tissue concentrations from the MRS data. These results will form the foundation of future studies of animal models of schizophrenia and patient studies correlating drug class, response, NAA levels and cognition. Such studies will make MRS a useful tool for the determination of both drug type and dose response in patients with psychiatric illnesses.