Unitat de Farmacologia, Departament Patologia i Terapeutica Experimental, Facultat de Medicina i Ciencies de la Salut, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
CNS Neurol Disord Drug Targets. 2018;17(7):522-527. doi: 10.2174/1871527317666180627103337.
Pridopidine, a compound in clinical trials for Huntington's disease treatment, was originally synthesized as a dopamine D2 receptor (D2R) ligand, but later found to possess higher affinity for the sigma-1 receptor (S1R). However, the putative contributions of D2R and S1R to the behavioral profile of acutely administered pridopidine have not been investigated.
The present study sought to compare the effects of acute pridopidine on wild-type vs. D2R and S1R knockout mice, at high (60 mg/kg) and low (6 mg/kg) doses.
Pridopidine effects on basal and phencyclidine-induced locomotor activity was measured in the open field test. Additionally, the actions of pridopidine on prepulse inhibition was measured in animals treated with saline or phencyclidine.
Whereas inhibition of spontaneous and phencyclidine-induced locomotion was readily observed at 60 mg/kg pridopidine, neither locomotor stimulation in habituated mice, nor any effects on prepulse inhibition were detected upon pridopidine treatment. Surprisingly, inhibition of spontaneous locomotion was unaffected by both D2R and S1R deletion.
The present results suggest the involvement of additional targets, besides D2R and S1R, in mediating locomotor inhibition by pridopidine.
普里多吡啶是一种正在进行临床试验的亨廷顿病治疗药物，最初被合成作为一种多巴胺 D2 受体（D2R）配体，但后来发现其对 sigma-1 受体（S1R）具有更高的亲和力。然而，急性给予普里多吡啶时 D2R 和 S1R 对其行为特征的潜在作用尚未得到研究。
本研究旨在比较急性给予普里多吡啶对野生型和 D2R 和 S1R 敲除小鼠的影响，剂量分别为高（60mg/kg）和低（6mg/kg）。
在开放场试验中测量普里多吡啶对基础和苯环利定诱导的运动活动的影响。此外，还在接受生理盐水或苯环利定治疗的动物中测量普里多吡啶对前脉冲抑制的作用。
虽然在 60mg/kg 普里多吡啶时可观察到对自发性和苯环利定诱导的运动的抑制作用，但在习惯化小鼠中既未观察到运动刺激，也未观察到普里多吡啶治疗后的任何前脉冲抑制作用。令人惊讶的是，自发性运动的抑制不受 D2R 和 S1R 缺失的影响。
本研究结果表明，除了 D2R 和 S1R 之外，普里多吡啶介导的运动抑制作用还涉及其他靶点。
