The doparnine D3 receptor antagonist NGB 2904 increases spontaneous and amphetamine-stimulated locomotion
The doparnine D3 receptor antagonist NGB 2904 increases spontaneous and amphetamine-stimulated locomotion
复制标题
DOI：
10.1016/j.pbb.2007.02.019
复制
发表时间：
2007-04-01
影响因子：
3.6
通讯作者：
Richtand, Neil M.
中科院分区：
文献类型：
--
作者：
Pritchard, Laurel M.;Newman, Amy Hauck;Richtand, Neil M.
多巴胺D3受体被认为在啮齿动物运动行为的调节中起重要作用，并且已被提议作为药物滥用、精神障碍和帕金森病的治疗靶点。多巴胺D3受体功能的一个模型，基于使用D3受体敲除小鼠和D3受体偏好激动剂的研究，提出D3受体刺激抑制精神兴奋剂诱导的运动，与同时多巴胺D1和D2受体刺激的作用相反。药物化学的最新进展导致了高选择性多巴胺D3受体拮抗剂的发展。为了扩展我们对D3多巴胺受体的行为功能的理解，我们确定了高选择性多巴胺D3受体拮抗剂NGB 2904对野生型和多巴胺D3受体敲除小鼠的安非他明刺激和自发运动的影响。NGB 2904（26.0 μ g/kg s.c.）在野生型小鼠中增强安非他明刺激的运动，但在多巴胺D3受体敲除小鼠中没有可测量的效果。在急性给药或每天一次给药7天的一系列剂量（0.026 μ g-1.0 mg/kg）中，最高剂量的NGB 2904（1.0 mg/kg）刺激野生型小鼠的自发运动，但在多巴胺D3受体敲除小鼠中没有可测量的作用。NGB 2904的这些行为效应与其他高度D3受体选择性拮抗剂所描述的那些形成对比，这些受体选择性拮抗剂先前未证明对自发运动活性的影响。在组合中，这些数据添加到这种新的D3受体配体的行为特征，并提供进一步的支持多巴胺D3受体抑制功能在啮齿动物运动的调制中的作用。(c)2007爱思唯尔公司All rights reserved.
The dopamine D3 receptor is believed to play an important role in regulation of rodent locomotor behavior, and has been proposed as a therapeutic target for substance abuse, psychotic disorders, and Parkinson's disease. One model of dopamine D3 receptor function, based on studies utilizing D3 receptor knockout mice and D3 receptor-preferring agonists, proposes that D3 receptor stimulation is inhibitory to psychostimulant-induced locomotion, in opposition to the effects of concurrent dopamine D1 and D2 receptor stimulation. Recent progress in medicinal chemistry has led to the development of highly-selective dopamine D3 receptor antagonists. In order to extend our understanding of D3 dopamine receptor's behavioral functions, we determined the effects of the highly-selective dopamine D3 receptor antagonist NGB 2904 on amphetamine-stimulated and spontaneous locomotion in wild-type and dopamine D3 receptor knockout mice. NGB 2904 (26.0 mu g/kg s.c.) enhanced amphetamine-stimulated locomotion in wild-type mice, but had no measurable effect in dopamine D3 receptor knockout mice. Of a range of doses (0.026 mu g-1.0 mg/kg) given acutely or once daily for seven days, the highest dose of NGB 2904 (1.0 mg/kg) stimulated spontaneous locomotion in wild-type mice, but was without measurable effect in dopamine D3 receptor knockout mice. These behavioral effects of NGB 2904 contrast with those described for other highly D3 receptor-selective antagonists, which have not previously demonstrated an effect on spontaneous locomotor activity. In combination, these data add to the behavioral profile of this novel D3 receptor ligand and provide further support for a role for dopamine D3 receptor inhibitory function in the modulation of rodent locomotion. (c) 2007 Elsevier Inc. All rights reserved.