Waters Susanna, Ponten Henrik, Edling Malin, Svanberg Boel, Klamer Daniel, Waters Nicholas
Department of Pharmacology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 431, 405 30, Gōteborg, Sweden,
J Neural Transm (Vienna). 2014 Nov;121(11):1337-47. doi: 10.1007/s00702-014-1231-1. Epub 2014 May 11.
The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-D-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.
多巴胺能稳定剂普立多匹定[4-(3-(甲基磺酰基)phenyl)-1-丙基哌啶]和奥多匹定[1-乙基-4-(2-氟-3-(甲基磺酰基)phenyl)哌啶]可抑制精神兴奋剂诱发的多动，并刺激活动不足状态下的行为。虽然这两种化合物在体外均作为多巴胺D2受体拮抗剂起作用，尽管亲和力较低，但它们特定的状态依赖性行为效应谱并非一般的D2受体拮抗剂所共有。为了进一步了解普立多匹定和奥多匹定的神经药理学作用，以及它们在体内与其他多巴胺能化合物的差异，我们评估了活动调节细胞骨架相关蛋白/活动调节基因3.1（Arc）的表达，Arc是一种与突触激活相关的即刻早期基因标记物，在额叶皮质和纹状体中进行了评估。此外，还评估了单胺神经化学和运动活性。将普立多匹定和奥多匹定的作用与参考多巴胺D1和D2受体激动剂和拮抗剂，以及部分多巴胺D2激动剂阿立哌唑进行了比较。普立多匹定和奥多匹定诱导皮质Arc表达显著增加，相对于对照组分别达到2.2倍和1.7倍水平。相比之下，所测试的参考多巴胺D1和D2化合物均未增加皮质Arc表达。在纹状体中，普立多匹定、奥多匹定以及多巴胺D2受体拮抗剂瑞莫必利和氟哌啶醇均使Arc表达显著增加。有趣的是，纹状体Arc表达与纹状体3,4-二羟基苯乙酸呈强烈正相关，表明多巴胺D2受体拮抗作用可增加纹状体中Arc的表达。总之，普立多匹定和奥多匹定诱导的皮质和纹状体Arc表达同时增加似乎是多巴胺能稳定剂所特有的,因为所测试的参考化合物并未出现这种情况。皮质Arc表达的增加被推测反映了额叶皮质中N-甲基-D-天冬氨酸受体介导的信号增强，这可能有助于普立多匹定和奥多匹定的状态依赖性运动效应。
