Higgins Guy A, Silenieks Leo B, MacMillan Cam, Sevo Julia, Zeeb Fiona D, Thevarkunnel Sandy
InterVivo Solutions Inc, 120 Carlton Street, Toronto, ON M5A 4K2, Canada; Dept. Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
InterVivo Solutions Inc, 120 Carlton Street, Toronto, ON M5A 4K2, Canada.
Behav Brain Res. 2016 Sep 15;311:1-14. doi: 10.1016/j.bbr.2016.05.025. Epub 2016 May 11.
NMDA GluN2B (NR2B) subtype selective antagonists are currently in clinical development for a variety of indications, including major depression. We previously reported the selective NMDA GluN2B antagonists Ro 63-1908 and traxoprodil, increase premature responding in a 5-choice serial reaction time task (5-CSRTT) suggesting an effect on impulsive action. The present studies extend these investigations to a Go-NoGo and delay discounting task, and the 5-CSRTT under test conditions of both regular (5s) and short (2-5s) multiple ITI (Intertrial interval). Dizocilpine was included for comparison. Both Ro 63-1908 (0.1-1mg/kg SC) and traxoprodil (0.3-3mg/kg SC) increased premature and perseverative responses in both 5-CSRT tasks and improved attention when tested under a short ITI test condition. Ro 63-1908 but not traxoprodil increased motor impulsivity (false alarms) in a Go-NoGo task. Dizocilpine (0.01-0.06mg/kg SC) affected both measures of motor impulsivity and marginally improved attention. In a delay discounting test of impulsive choice, both dizocilpine and Ro 63-1908 decreased impulsive choice (increased choice for the larger, delayed reward), while traxoprodil showed a similar trend. Motor stimulant effects were evident following Ro 63-1908, but not traxoprodil treatment - although no signs of motor stereotypy characteristic of dizocilpine (>0.1mg/kg) were noted. The findings of both NMDA GluN2B antagonists affecting measures of impulsive action and compulsive behavior may underpin emerging evidence to suggest glutamate signaling through the NMDA GluN2B receptor plays an important role in behavioural flexibility. The profiles between Ro 63-1908 and traxoprodil were not identical, perhaps suggesting differences between members of this drug class.
N-甲基-D-天冬氨酸（NMDA）谷氨酸能受体2B（GluN2B，NR2B）亚型选择性拮抗剂目前正处于针对包括重度抑郁症在内的多种适应症的临床开发阶段。我们之前报道过，选择性NMDA GluN2B拮抗剂Ro 63-1908和曲唑生，在一项5选串行反应时任务（5-CSRTT）中增加了过早反应，提示对冲动行为有影响。本研究将这些调查扩展至一项Go-NoGo任务、延迟折扣任务以及在常规（5秒）和短（2 - 5秒）多重刺激间隔（ITI）测试条件下的5-CSRTT。加入地卓西平作为对照。Ro 63-1908（0.1 - 1毫克/千克，皮下注射）和曲唑生（0.3 - 3毫克/千克，皮下注射）在短ITI测试条件下进行测试时，在两项5-CSRT任务中均增加了过早和持续性反应，并改善了注意力。Ro 63-1908而非曲唑生在一项Go-NoGo任务中增加了运动冲动性（误报）。地卓西平（0.01 - 0.06毫克/千克，皮下注射）影响了运动冲动性的两项指标，并在一定程度上改善了注意力。在一项冲动选择的延迟折扣测试中，地卓西平和Ro 63-1908均减少了冲动选择（增加了对更大、延迟奖励的选择），而曲唑生显示出类似趋势。Ro 63-1908给药后出现了运动兴奋作用，但曲唑生给药后未出现——尽管未观察到地卓西平（>0.1毫克/千克）特有的运动刻板行为迹象。两种NMDA GluN2B拮抗剂均影响冲动行为和强迫行为指标的这一发现，可能支持了新出现的证据，表明通过NMDA GluN2B受体的谷氨酸信号传导在行为灵活性中起重要作用。Ro 63-1908和曲唑生的表现并不相同，这可能表明该药物类别的成员之间存在差异。
