CNS Department, Sanofi-Aventis Research & Development, Bagneux, France.
Neuropsychopharmacology. 2010 Jan;35(2):416-27. doi: 10.1038/npp.2009.144.
Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. However, the observation that antagonists of the glutamate N-methyl-D-aspartate (NMDA) receptor produce schizophrenic-like symptoms in humans has led to the idea of a dysfunctioning of the glutamatergic system via its NMDA receptor. As a result, there is a growing interest in the development of pharmacological agents with potential antipsychotic properties that enhance the activity of the glutamatergic system via a modulation of the NMDA receptor. Among them are glycine transporter-1 (GlyT1) inhibitors such as SSR103800, which indirectly enhance NMDA receptor function by increasing the glycine (a co-agonist for the NMDA receptor) levels in the synapse. This study aimed at investigating the potential antipsychotic-like properties of SSR103800, with a particular focus on models of hyperactivity, involving either drug challenge (ie, amphetamine and MK-801) or transgenic mice (ie, NMDA Nr1(neo-/-) and DAT(-/-)). Results showed that SSR103800 (10-30 mg/kg p.o.) blocked hyperactivity induced by the non-competitive NMDA receptor antagonist, MK-801 and partially reversed spontaneous hyperactivity of NMDA Nr1(neo-/-) mice. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT(-/-)) knockout mice (10-30 mg/kg p.o.). Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. Together these findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs.
精神分裂症最初与多巴胺神经传递功能障碍有关。然而，观察到谷氨酸 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂在人类中产生类似精神分裂症的症状，这导致了通过其 NMDA 受体使谷氨酸能系统功能障碍的想法。因此，人们越来越关注开发具有潜在抗精神病特性的药理学制剂，通过调节 NMDA 受体来增强谷氨酸能系统的活性。其中包括甘氨酸转运蛋白-1 (GlyT1) 抑制剂，如 SSR103800，它通过增加突触中的甘氨酸（NMDA 受体的共激动剂）水平间接增强 NMDA 受体功能。本研究旨在研究 SSR103800 的潜在抗精神病特性，特别关注涉及药物挑战（即安非他命和 MK-801）或转基因小鼠（即 NMDA Nr1(neo-/-) 和 DAT(-/-)）的过度活跃模型。结果表明，SSR103800（10-30 mg/kg p.o.）阻断了非竞争性 NMDA 受体拮抗剂 MK-801 诱导的过度活跃，并部分逆转了 NMDA Nr1(neo-/-) 小鼠的自发性过度活跃。相比之下，SSR103800 未能影响安非他命或多巴胺转运体 (DAT(-/-)) 敲除小鼠（10-30 mg/kg p.o.）自然观察到的过度活跃。重要的是，经典（氟哌啶醇）和非典型（奥氮平、氯氮平和阿立哌唑）抗精神病药在所有这些过度活跃模型中都有效。然而，与这些药物不同的是，SSR103800 在高达 30 mg/kg p.o. 的剂量下不会产生僵住（棒测试保留）。这些发现表明，GlyT1 抑制剂 SSR103800 产生抗精神病作用，与主要针对多巴胺能系统的化合物观察到的作用不同，并且与这些药物相比，其副作用潜力降低。
