Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Eli Lilly and Company, Indianapolis, IN 46285, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA; Department of Radiological and Imaging Sciences, Indiana University School of Medicine, Indiana University - Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Eur Neuropsychopharmacol. 2018 Sep;28(9):1035-1046. doi: 10.1016/j.euroneuro.2018.05.016. Epub 2018 Jul 10.
One of the major challenges of cross-species translation in psychiatry is the identification of quantifiable brain phenotypes linked to drug efficacy and/or side effects. A measure that has received increasing interest is the effect of antipsychotic drugs on resting-state functional connectivity (FC) in magnetic resonance imaging. However, quantitative comparisons of antipsychotic drug-induced alterations of FC patterns are missing. Consideration of receptor binding affinities provides a means for the effects of antipsychotic drugs on extended brain networks to be related directly to their molecular mechanism of action. Therefore, we examined the relationship between the affinities of three second-generation antipsychotics (amisulpride, risperidone and olanzapine) to dopamine and serotonin receptors and FC patterns related to the prefrontal cortex (PFC) and striatum in Sprague-Dawley rats. FC of the relevant regions was quantified by correlation coefficients and local network properties. Each drug group (32 animals per group) was subdivided into three dose groups and a vehicle control group. A linear relationship was discovered for the mid-dose of antipsychotic compounds, with stronger affinity to serotonin 5-HT, 5-HT and 5-HT receptors and decreased affinity to D receptors associated with increased prefrontal-striatal FC (p = 0.0004, r² = 0.46; p = 0.004, r² = 0.33; p = 0.002, r² = 0.37; p = 0.02, r² = 0.22, respectively). Interestingly, no correlation was observed for the low and high dose groups, and for D receptors. Our results indicate that drug-induced FC patterns may be linked to antipsychotic mechanism of action on the molecular level and suggest the technique's value for drug development, especially if our results are extended to a larger number of antipsychotics.
精神科跨物种翻译的主要挑战之一是确定与药物疗效和/或副作用相关的可量化的大脑表型。越来越受到关注的一个衡量标准是抗精神病药物对磁共振成像中静息状态功能连接 (FC) 的影响。然而，目前缺乏定量比较抗精神病药物诱导的 FC 模式变化。考虑受体结合亲和力为将抗精神病药物对扩展大脑网络的影响直接与其作用机制联系起来提供了一种手段。因此，我们研究了三种第二代抗精神病药物（氨磺必利、利培酮和奥氮平）对多巴胺和 5-羟色胺受体的亲和力与相关脑区功能连接 (FC) 模式之间的关系，这些脑区与前额叶皮层（PFC）和纹状体有关。通过相关区域的相关系数和局部网络特性来量化 FC。每组药物（每组 32 只动物）分为三个剂量组和一个载体对照组。发现抗精神病化合物的中剂量与 5-HT、5-HT 和 5-HT 受体的亲和力呈线性关系，与 D 受体的亲和力降低与前额叶-纹状体 FC 增加相关（p = 0.0004，r² = 0.46;p = 0.004，r² = 0.33;p = 0.002，r² = 0.37;p = 0.02，r² = 0.22，分别）。有趣的是，低剂量和高剂量组以及 D 受体均未观察到相关性。我们的结果表明，药物诱导的 FC 模式可能与抗精神病药物的作用机制在分子水平上有关，并表明该技术在药物开发方面的价值，特别是如果我们的结果扩展到更多数量的抗精神病药物。
