The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity
The affinity of antipsychotic drugs to dopamine and serotonin 5-HT2 receptors determines their effects on prefrontal-striatal functional connectivity
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DOI：
10.1016/j.euroneuro.2018.05.016
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发表时间：
2018-09
影响因子：
5.6
通讯作者：
F. Tollens;N. Gass;Robert Becker;A. J. Schwarz;A. J. Schwarz;A. J. Schwarz;C. Risterucci;Basil Künnecke;P. Lebhardt;J. Reinwald;Markus Sack;W. Weber-Fahr;A. Meyer-Lindenberg;Alexander Sartorius
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文献类型：
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作者：
F. Tollens;N. Gass;Robert Becker;A. J. Schwarz;A. J. Schwarz;A. J. Schwarz;C. Risterucci;Basil Künnecke;P. Lebhardt;J. Reinwald;Markus Sack;W. Weber-Fahr;A. Meyer-Lindenberg;Alexander Sartorius
精神病学中跨物种翻译的主要挑战之一是识别与药物疗效和/或副作用相关的可量化的大脑表型。抗精神病药物对磁共振成像中静息态功能连接（FC）的影响是一个越来越受关注的指标。然而，抗精神病药物引起的FC模式的改变的定量比较缺失。受体结合亲和力的考虑提供了一种手段，抗精神病药物对扩展脑网络的影响直接与其分子作用机制有关。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）与多巴胺和5-羟色胺受体的亲和力以及与Sprague-Dawley大鼠前额叶皮质（PFC）和纹状体相关的FC模式之间的关系。通过相关系数和局部网络性质对相关区域的FC进行量化。将每个药物组（每组32只动物）再分为三个剂量组和一个溶剂对照组。发现中等剂量的抗精神病药物与5-HT 2A、5-HT 2C和5-HT 1A受体的亲和力较强，与D3受体的亲和力降低，与前额叶-纹状体FC增加相关，呈线性关系（p= 0.0004，r ² = 0.46;p= 0.004，r ² = 0.33;p= 0.002，r ² = 0.37;p= 0.02，r ² = 0.22）。有趣的是，在低剂量组和高剂量组以及D2受体中未观察到相关性。我们的研究结果表明，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，并建议该技术的药物开发的价值，特别是如果我们的研究结果扩展到更多的抗精神病药物。
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-HT2A, 5-HT2Cand 5-HT1Areceptors and decreased affinity to D3receptors 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 D2receptors. 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.