Antipsychotic effects on N-acetyl aspartate in rat brain

描述(申请人提供)：抗精神病药物主要用于治疗精神分裂症，尽管它们也越来越多地用于治疗其他精神疾病。这些药物的作用机制还不是很清楚，也没有很好的治疗反应预测指标。为了解决这一认识上的差距，我们正在应用磁共振波谱(MRS)作为一种工具来调查和监测抗精神病药物的效果。我们的目标是将抗精神病药物对MRS信号的影响与疾病的影响分开，这将为使用MRS监测和预测患者对抗精神病药物的反应提供基础。我们假设，与对照组相比，在高剂量的典型抗精神病药物氯氮平和非典型抗精神病药物氯氮平的长期治疗过程中，大鼠脑内NAA的组织浓度逐渐下降，但不是低剂量，并且氟哌啶醇的下降幅度将更大。这项建议的具体目的是在给药两种剂量水平的氟哌啶醇、氯氮平或对照溶液之前和期间，量化正常大鼠脑组织中NAA的浓度。 我们主要对NAA感兴趣，这是一种在精神分裂症中改变的神经元健康的生物标志物。抗精神病药物治疗对NAA的MRS测量的影响尚不清楚。几项MRS研究表明，在抗精神病药物治疗后，NAA水平下降。然而，其他研究报告称，治疗后对NAA没有影响。我们在大鼠大脑中使用MRS的初步结果表明，在低剂量抗精神病药物治疗后，NAA水平没有短期变化。抗精神病药物给药后NAA水平的MRS测量的剂量和时间依赖性都没有得到系统的研究。我们计划解决这个问题，并通过扩展我们的初步发现来检验我们的假设。我们将每月从接受两种剂量氟哌啶醇、氯氮平或对照溶液之一的大鼠的大脑中获取MRS数据，连续六个月。我们将根据MRS数据计算NAA组织浓度。这些结果将为未来精神分裂症动物模型的研究以及与药物类别、反应、NAA水平和认知相关的患者研究奠定基础。这些研究将使MRS成为一种有用的工具，用于确定精神病患者的药物类型和剂量反应。

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.