De Montfort University, Leicester School of Pharmacy, The Gateway, Leicester, LE1 9BH, UK.
J Neural Transm (Vienna). 2013 Sep;120(9):1281-94. doi: 10.1007/s00702-013-1002-4. Epub 2013 Mar 7.
The dopaminergic stabilizer pridopidine demonstrates state-dependent effects on locomotor activity, counteracting both hypo- and hyperactivity in rats. Pridopidine has been shown to display both functional dopamine D2 receptor antagonist properties and increase in biomarkers associated with NMDA-mediated glutamate transmission in the frontal cortex. To further characterise the effects of pridopidine on prefrontal cortex (PFC) neurons, a series of in vivo electrophysiological studies were performed in urethane-anaesthetised rats. Pridopidine, administered at doses from 10 to 60 mg/kg (i.v.), dose dependently increased pyramidal cell firing in the majority of the neurons tested. Pridopidine induced a significant increase of 162 % in mean firing activity of PFC neurons, versus initial basal firing activity as the cumulative dose of 30 mg/kg, i.v., was administered. This enhancement of activity was due to increased firing frequency of already spontaneously active neurons, rather than an increase in population activity. The increase was partially reversed or prevented by a sub-threshold dose of the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg, i.v.). Microiontophoretic application of pridopidine had only moderate activating effects. The selective dopamine D1 receptor agonist A-68930 also had limited effects when administered by microiontophoretic application, but exerted a dose dependent (0.2-3 mg/kg, i.v.) activation of firing in the majority of neurons tested (10/16). However, inhibition of firing by systemic administration of A-68930 was also observed in a subgroup of neurons (6/16). Both activation and inhibition of firing induced by systemic administration of A-68930 were reversed by the systemic administration of SCH23390. The present data suggests that pridopidine enhances pyramidal cell firing via an indirect dopamine D1 receptor-mediated mechanism. These effects of pridopidine may serve to strengthen the cortico-striatal communication and to improve motor control in Huntington's disease for which pridopidine is currently in development.
多巴胺稳定剂普里多吡啶（Pridopidine）对运动活动表现出状态依赖性效应，可对抗大鼠的低活动和高活动。已显示普里多吡啶既具有功能性多巴胺 D2 受体拮抗剂特性，又能增加与额皮质中 NMDA 介导的谷氨酸传递相关的生物标志物。为了进一步描述普里多吡啶对前额皮质（PFC）神经元的影响，在乌拉坦麻醉的大鼠中进行了一系列体内电生理学研究。普里多吡啶以 10 至 60mg/kg（静脉内）的剂量给药，剂量依赖性地增加了大多数测试神经元的锥体细胞放电。与静脉内给予 30mg/kg 累积剂量时的初始基础放电活动相比，普里多吡啶诱导 PFC 神经元的平均放电活性显著增加 162％。这种活性的增强是由于已经自发活跃的神经元的放电频率增加，而不是群体活性的增加。亚阈值剂量的多巴胺 D1 受体拮抗剂 SCH23390（0.5mg/kg，静脉内）部分逆转或预防了这种增加。微电泳应用普里多吡啶仅有适度的激活作用。选择性多巴胺 D1 受体激动剂 A-68930 经微电泳应用时也具有有限的作用，但对大多数测试神经元（10/16）表现出剂量依赖性（0.2-3mg/kg，静脉内）的激活作用。然而，在一组亚群神经元中也观察到全身性给予 A-68930 抑制放电。通过全身性给予 A-68930 诱导的放电激活和抑制均通过全身性给予 SCH23390 逆转。目前的数据表明，普里多吡啶通过间接的多巴胺 D1 受体介导的机制增强锥体细胞放电。普里多吡啶的这些作用可能有助于加强皮质纹状体的通讯，并改善亨廷顿病的运动控制，普里多吡啶目前正在开发中。
