Pritchard Laurel M, Newman Amy Hauck, McNamara Robert K, Logue Aaron D, Taylor Benjamin, Welge Jeffrey A, Xu Ming, Zhang Jianhua, Richtand Neil M
Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA.
Pharmacol Biochem Behav. 2007 Apr;86(4):718-26. doi: 10.1016/j.pbb.2007.02.019. Epub 2007 Mar 6.
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 microg/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 microg-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.
多巴胺D3受体被认为在调节啮齿动物的运动行为中起重要作用，并已被提议作为药物滥用、精神疾病和帕金森病的治疗靶点。基于利用D3受体基因敲除小鼠和D3受体选择性激动剂的研究，一种多巴胺D3受体功能模型提出，与同时刺激多巴胺D1和D2受体的作用相反，D3受体刺激对精神兴奋剂诱导的运动具有抑制作用。药物化学的最新进展导致了高选择性多巴胺D3受体拮抗剂的开发。为了扩展我们对D3多巴胺受体行为功能的理解，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受体基因敲除小鼠中苯丙胺刺激的运动和自发运动的影响。NGB 2904（26.0微克/千克，皮下注射）增强了野生型小鼠中苯丙胺刺激的运动，但对多巴胺D3受体基因敲除小鼠没有可测量的影响。在急性给予或连续七天每天一次给予的一系列剂量（0.026微克-1.0毫克/千克）中，NGB 2904的最高剂量（1.0毫克/千克）刺激了野生型小鼠的自发运动，但对多巴胺D3受体基因敲除小鼠没有可测量的影响。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效应形成对比，这些拮抗剂以前未显示对自发运动活动有影响。综合来看，这些数据增加了这种新型D3受体配体的行为特征，并为多巴胺D3受体抑制功能在调节啮齿动物运动中的作用提供了进一步支持。
