Singer Philipp, Feldon Joram, Yee Benjamin K
Laboratory of Behavioral Neurobiology, Swiss Federal Institute of Technology Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Eur Neuropsychopharmacol. 2009 Aug;19(8):571-80. doi: 10.1016/j.euroneuro.2009.02.004. Epub 2009 Mar 17.
The specific glycine transporter 1 (GlyT1) inhibitor, SSR504734, is highly effective in enhancing N-methyl-D-aspartate receptor (NMDAR) function by elevating the availability of the NMDAR co-agonist, glycine, in the vicinity of NMDAR-containing glutamatergic synapses. According to the glutamatergic hypofunction hypothesis of schizophrenia, SSR504734 may therefore possess antipsychotic potential. Here, we evaluated the effects of SSR504734 in response to three psychomimetic drugs: phencyclidine, amphetamine, and apomorphine in male C57BL/6 mice. SSR504734 attenuated phencyclidine-induced (5 mg/kg, i.p.) hyperlocomotion, but potentiated the motor stimulant and motor depressant effects of amphetamine (2.5 mg/kg, i.p.) and apomorphine (0.75 mg/kg, s.c.), respectively. Hence, SSR504734 not only confers resistance to NMDAR blockade, but also enhances the locomotor response to dopaminergic stimulation. The latter finding adds to reports that SSR504734 may modulate dopamine-mediated behaviour by interference with normal glutamate-dopamine interaction. The specificity of this action of SSR504734 will be highly relevant to its potential application as an antipsychotic agent.
特异性甘氨酸转运体1（GlyT1）抑制剂SSR504734通过提高含N-甲基-D-天冬氨酸受体（NMDAR）的谷氨酸能突触附近NMDAR共激动剂甘氨酸的可用性，在增强NMDAR功能方面具有高效性。根据精神分裂症的谷氨酸能功能减退假说，因此SSR504734可能具有抗精神病潜力。在此，我们评估了SSR504734对雄性C57BL/6小鼠体内三种拟精神病药物：苯环利定、苯丙胺和阿扑吗啡的反应效果。SSR504734减弱了苯环利定（5毫克/千克，腹腔注射）诱导的运动亢进，但分别增强了苯丙胺（2.5毫克/千克，腹腔注射）和阿扑吗啡（0.75毫克/千克，皮下注射）的运动兴奋和运动抑制作用。因此，SSR504734不仅赋予对NMDAR阻断的抗性，还增强了对多巴胺能刺激的运动反应。后一发现补充了关于SSR504734可能通过干扰正常谷氨酸-多巴胺相互作用来调节多巴胺介导行为的报道。SSR504734这一作用的特异性与其作为抗精神病药物的潜在应用高度相关。
