Antipsychotic effects on N-acetyl aspartate in rat brain

描述（由申请人提供）：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清楚，也没有很好的预测治疗反应。为了解决这一知识缺口，我们正在应用磁共振波谱（MRS）作为调查和监测抗精神病药物作用的工具。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，在长期治疗期间，高剂量的典型抗精神病药物氟哌啶醇和非典型抗精神病药物氯氮平，而不是低剂量，大鼠脑中NAA的组织浓度逐渐降低，并且氟哌啶醇的降低幅度更大。本建议的具体目的是量化的NAA组织浓度在正常大鼠脑前和期间的两个剂量水平的氟哌啶醇，氯氮平，或控制解决方案。 我们主要对NAA感兴趣，这是精神分裂症中神经元健康的生物标志物。抗精神病药物治疗对NAA MRS测量的影响尚不清楚。一些MRS研究表明，抗精神病药物治疗后NAA水平下降。然而，其他研究报告治疗后对NAA没有影响。我们的初步研究结果表明，在大鼠脑中使用MRS没有短期的变化发生在NAA水平低剂量的抗精神病药物。抗精神病药物给药后NAA水平的MRS测量的剂量依赖性和时间依赖性均未得到系统研究。我们计划解决这个问题，并通过扩展我们的初步发现来测试我们的假设。 我们将每月从每天接受两种剂量的氟哌啶醇、氯氮平或对照溶液中的一种的大鼠大脑中获取MRS数据，持续6个月。我们将从MRS数据计算NAA组织浓度。这些结果将为今后精神分裂症动物模型的研究和与药物类别、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成为确定精神疾病患者药物类型和剂量反应的有用工具。

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.