Department of Physiology and Pharmacology, The Karolinska Institutet, Stockholm, Sweden.
Psychopharmacology (Berl). 2012 May;221(1):115-31. doi: 10.1007/s00213-011-2554-3. Epub 2011 Nov 9.
The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive allosteric modulators (AMPA-PAMs), Org 24448 and Org 26576, and the glycine transporter-1 (GlyT-1) inhibitor Org 25935 are developed for treatment of schizophrenia.
Here we examined experimentally the ability of co-administration of these AMPA-PAMs or the GlyT-1 inhibitor to augment the antipsychotic activity and effect on cortical N-methyl-D: -aspartate (NMDA) receptor-mediated transmission of risperidone, olanzapine, or haloperidol.
We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect liability using a catalepsy test, and cortical NMDA receptor-mediated glutamatergic transmission using intracellular electrophysiological recording technique in vitro.
Both AMPA-PAMs enhanced the suppression of CAR induced by risperidone or olanzapine, and Org 24448 also enhanced the effect of haloperidol. In contrast, the GlyT-1 inhibitor did not cause any behaviorally significant effect in the CAR test. However, the GlyT-1 inhibitor, but not the AMPA-PAMs, produced a large facilitation of NMDA-induced currents. All three drugs potentiated the effect of risperidone but not haloperidol on these currents. The GlyT-1 inhibitor also facilitated the effect of olanzapine. All drugs potentiated the effect of risperidone on electrically stimulated excitatory postsynaptic potentials (EPSP) in cortical pyramidal cells, whereas only the GlyT inhibitor facilitated the effect of olanzapine.
Our results suggest that the AMPA-PAMs, when compared to the GlyT-1 inhibitor, show differential effects in terms of augmentation of antipsychotic efficacy, particularly when combined with risperidone or olanzapine. Both AMPA-PAMs and the GlyT-1 inhibitor may also improve negative symptoms and cognitive impairments in schizophrenia, in particular when combined with risperidone.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体正变构调节剂（AMPA-PAMs），Org 24448 和 Org 26576，以及甘氨酸转运体-1（GlyT-1）抑制剂 Org 25935，是为治疗精神分裂症而开发的。
在这里，我们实验性地检查了联合使用这些 AMPA-PAMs 或 GlyT-1 抑制剂是否能够增强利培酮、奥氮平或氟哌啶醇的抗精神病活性和对皮质 N-甲基-D：-天冬氨酸（NMDA）受体介导的传递的作用。
我们使用条件回避反应（CAR）测试检查抗精神病疗效，使用僵住测试检查锥体外系副作用倾向，使用细胞内电生理记录技术在体外检查皮质 NMDA 受体介导的谷氨酸能传递。
两种 AMPA-PAMs 均增强了利培酮或奥氮平诱导的 CAR 的抑制作用，Org 24448 还增强了氟哌啶醇的作用。相比之下，GlyT-1 抑制剂在 CAR 测试中没有引起任何行为上显著的效果。然而，GlyT-1 抑制剂而不是 AMPA-PAMs 引起 NMDA 诱导电流的大幅促进。三种药物均增强了利培酮的作用，但不增强氟哌啶醇的作用。GlyT-1 抑制剂还促进了奥氮平的作用。所有药物均增强了利培酮对皮质锥体神经元电刺激兴奋性突触后电位（EPSP）的作用，而只有 GlyT 抑制剂促进了奥氮平的作用。
我们的结果表明，与 GlyT-1 抑制剂相比，AMPA-PAMs 在增强抗精神病疗效方面表现出不同的作用，特别是与利培酮或奥氮平联合使用时。AMPA-PAMs 和 GlyT-1 抑制剂也可能改善精神分裂症的阴性症状和认知障碍，特别是与利培酮联合使用时。
