Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
J Neural Transm (Vienna). 2018 Apr;125(4):705-711. doi: 10.1007/s00702-017-1827-3. Epub 2017 Dec 21.
Diminished glutamate neurotransmission via the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been considered to be involved in the pathophysiology of schizophrenia based upon the observation that the antagonists and autoantibodies of NMDAR cause positive, negative and cognitive symptomatologies similar to those of schizophrenia. The possible reduced extracellular levels of D-serine by overstimulation of the calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor (CP-AMPAR) following the NMDAR hypofunction-induced compensatory increase in the glutamate release could aggravate the NMDAR hypofunction in the brain of the drug- or antibody-associated psychoses and schizophrenia, because D-serine is an intrinsic coagonist for the NMDAR. To obtain an insight into the therapeutic approach to such a glutamate-linked psychotic state, we have studied the effects of the systemic administration of the CP-AMPAR-selective antagonist, IEM 1460 (N,N,N-trimethyl-5- [(tricyclo[3.3.1.1]dec-1-ylmethyl)amino]-1-pentanaminium bromide hydrobromide), on the hyperactivity following an injection of a schizophrenomimetic NMDAR antagonist, phencyclidine, in the mouse. The subcutaneous IEM 1460 application produced a dose-dependent inhibition of the increased movement counts after the subcutaneous injection of phencyclidine. This inhibiting influence was also seen on the hyperactivity elicited by another NMDAR antagonist, dizocilpine. Moreover, the IEM 1460 administration attenuated the ability of a schizophrenomimetic dopamine agonist, methamphetamine, to increase spontaneous movements. These findings indicate that dysregulation of the CP-AMPAR could, at least in part, be implicated in the glutamate pathology of schizophrenia and/or related psychotic symptoms and be a potential target for the development of their novel treatment.
谷氨酸能神经传递通过 N-甲基-D-天冬氨酸型谷氨酸受体（NMDAR）减少已被认为是参与精神分裂症的病理生理学，根据的观察，NMDAR 的拮抗剂和自身抗体引起阳性，阴性和认知症状类似于精神分裂症。可能的细胞外 D-丝氨酸水平降低通过过度刺激钙通透性的 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸谷氨酸受体（CP-AMPAR）在 NMDAR 功能低下引起的谷氨酸释放的代偿性增加后可能加剧在药物或抗体相关精神病和精神分裂症的大脑中的 NMDAR 功能低下，因为 D-丝氨酸是 NMDAR 的内在共激动剂。为了深入了解这种与谷氨酸相关的精神病状态的治疗方法，我们研究了全身给予 CP-AMPAR 选择性拮抗剂，IEM 1460（N，N，N-三甲基-5- [三环[3.3.1.1]癸-1-基甲基]氨基]-1-戊胺溴化物氢溴化物）对注射精神分裂症样 NMDAR 拮抗剂苯环利定后小鼠过度活动的影响。皮下 IEM 1460 应用产生了对苯环利定皮下注射后增加的运动计数的剂量依赖性抑制。这种抑制作用也见于另一种 NMDAR 拮抗剂地卓西平引起的过度活动。此外，IEM 1460 给药减弱了精神分裂症样多巴胺激动剂苯丙胺增加自发运动的能力。这些发现表明 CP-AMPAR 的失调至少部分地涉及精神分裂症和/或相关精神病症状的谷氨酸病理学，并可能成为其新型治疗的潜在靶标。
