Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-I SSR504734, a potential new type of antipsychotic
Neurochemical, electrophysiological and pharmacological profiles of the selective inhibitor of the glycine transporter-I SSR504734, a potential new type of antipsychotic
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DOI：
10.1038/sj.npp.1300772
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发表时间：
2005-11-01
影响因子：
7.6
通讯作者：
Scatton, B
中科院分区：
文献类型：
--
作者：
Depoortère, R;Dargazanli, G;Scatton, B
非竞争性N-甲基-D-天冬氨酸（NMDA）阻断剂诱导人类精神分裂症样症状，可能是通过损害多巴胺能传递。因此，通过增加甘氨酸（谷氨酸的必需共激动剂）的细胞外水平来增强这种神经传递的化合物可能具有抗精神病活性。阻断甘氨酸转运蛋白-1（GlyT 1）可通过增加细胞外甘氨酸水平，增强谷氨酸能神经传递。SSR 504734是人、大鼠和小鼠GlyT 1的选择性可逆抑制剂（IC 50分别为18、15和38 nM），可逆地阻断甘氨酸的离体摄取（小鼠皮质匀浆：ID 50：5 mg/kg i. p.），快速且持续很长时间。在体内，其增加（最小有效剂量（MED）：3 mg/kg i. p.）细胞外水平的甘氨酸在大鼠前额皮质（PFC）。这导致增强的海马能神经传递，因为SSR 504734增强了大鼠海马切片中NMDA介导的兴奋性突触后电流（EPSC）（最小有效浓度（MEC）：0.5 μ M）和小鼠纹状体内甘氨酸诱导的旋转（MED：1 mg/kg i. p.）。它使海马和PFC功能减退大鼠模型的活动正常化（通过激活突触前CBi受体）：它逆转了海马切片中电诱发[H-3]乙酰胆碱释放的减少（MEC：10 nM）和PFC神经元放电的减少（MED：0.3 mg/kg i. v.）。在小鼠和大鼠中，SSR 504734可预防氯胺酮诱导的小鼠边缘区代谢活化，并分别逆转MK-801诱导的活动过度和EEG频谱能量增加（MED：10-30 mg/kg i. p.）。在精神分裂症模型中，它使DBA/2小鼠的自发前脉冲抑制缺陷正常化（MED：15 mg/kg i. p.），和逆转对d-苯丙胺的运动效应的超敏性和选择性注意缺陷（MED：1-3 mg/kg i. p.）在用苯环己哌啶处理的成年大鼠中。最后，它增加细胞外多巴胺在大鼠PFC（MED：10毫克/公斤腹腔注射）。该化合物在抑郁/焦虑模型中显示出额外的活性，例如小鼠的慢性轻度应激（10 mg/kg i. p.），与母亲分离的幼鼠的超声波呼救（MED：1 mg/kg s.c.），和大鼠异相睡眠潜伏期增加（MED：30 mg/kg i.p）。总之，SSR 504734是一种有效的选择性GlyT 1抑制剂，在精神分裂症、焦虑和抑郁模型中表现出活性。通过靶向精神分裂症的主要原因之一（低血压），预计它不仅对阳性症状有效，而且对阴性症状、认知缺陷和共病抑郁/焦虑状态也有效。
Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50 = 18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 mu M) and intrastriatal glycine-induced rotations in mice (MED: I mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CBi receptors): it reversed the decrease in electrically evoked [H-3]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p,), In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.