Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba, 260-8670, Japan.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba, 260-8670, Japan.
Psychopharmacology (Berl). 2017 Oct;234(20):3027-3036. doi: 10.1007/s00213-017-4695-5. Epub 2017 Jul 25.
The long-term administration of antipsychotics is known to induce dopamine supersensitivity psychosis (DSP). Although the mechanism of DSP involves mainly a compensatory upregulation of dopamine D2 receptors, the precise mechanisms underlying DSP are unknown. It is known that glutamatergic signaling plays a key role in psychosis. We thus conducted this study to investigate whether glutamatergic signaling plays a role in the development of DSP.
Haloperidol (0.75 mg/kg/day for 14 days) or vehicle was administered to rats via osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSP rats and non-DSP rats based on locomotion data. Tissue levels of glutamate, glutamine, glycine, L-serine, D-serine, and GABA and the protein expressions of N-methyl-D-aspartate receptors (NMDAR), glutamic acid decarboxylase (GAD), and serine hydroxymethyltransferase (SHMT) in the rat brain regions were examined.
In the DSP rats, the ratio of GABA to glutamate was significantly increased. In addition, the ratio of L-serine to glycine was increased. The striatal expressions of GAD and SHMT2 in the DSP rats were significantly increased. In contrast, the striatal expression of NMDAR2B in the non-DSP rats was significantly decreased.
The present study suggests that glutamatergic signaling is relatively decreased to GABA in DSP rats. Our results also showed that excessive doses of haloperidol can induce striatal NMDAR hypofunction in non-DSP rats, which could prevent the formation of tardive dyskinesia but cause treatment resistance. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, further research exploring our present findings is necessary.
长期服用抗精神病药物会导致多巴胺超敏性精神病（DSP）。尽管 DSP 的机制主要涉及多巴胺 D2 受体的代偿性上调，但 DSP 的确切机制尚不清楚。已知谷氨酸能信号在精神病中起关键作用。因此，我们进行了这项研究，以调查谷氨酸能信号是否在 DSP 的发展中起作用。
通过渗透微型泵向大鼠给予氟哌啶醇（0.75mg/kg/天，共 14 天）或载体。根据运动数据，将氟哌啶醇处理的大鼠分为 DSP 大鼠组和非 DSP 大鼠组。检查大鼠大脑区域的谷氨酸、谷氨酰胺、甘氨酸、L-丝氨酸、D-丝氨酸和 GABA 的组织水平以及 N-甲基-D-天冬氨酸受体（NMDAR）、谷氨酸脱羧酶（GAD）和丝氨酸羟甲基转移酶（SHMT）的蛋白表达。
在 DSP 大鼠中，GABA 与谷氨酸的比值显著增加。此外，L-丝氨酸与甘氨酸的比值增加。DSP 大鼠纹状体的 GAD 和 SHMT2 表达显著增加。相比之下，非 DSP 大鼠纹状体的 NMDAR2B 表达显著降低。
本研究表明，DSP 大鼠中谷氨酸能信号相对 GABA 减少。我们的结果还表明，大剂量氟哌啶醇可在非 DSP 大鼠中诱导纹状体 NMDAR 功能低下，这可能预防迟发性运动障碍的形成，但导致治疗抵抗。鉴于治疗抵抗性精神分裂症的治疗策略的需要，有必要进一步研究探索我们目前的发现。
