Alterations in glutamatergic signaling in the brain of dopamine supersensitivity psychosis and non-supersensitivity psychosis model rats.
Alterations in glutamatergic signaling in the brain of dopamine supersensitivity psychosis and non-supersensitivity psychosis model rats.
复制标题
多巴胺超敏性精神病和非超敏性精神病模型大鼠大脑中谷氨酸信号的改变。
DOI：
10.1007/s00213-017-4695-5
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Iyo M.
中科院分区：
文献类型：
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作者：
Oda Y;Fujita Y;Oishi K;Nakata Y;Takase M;Niitsu T;Kanahara N;Shirayama Y;Hashimoto K;Iyo M.
背景长期服用抗精神病药物可诱发多巴胺超敏感性精神病（DSP）。虽然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。众所周知，谷氨酸能信号在精神病中起着关键作用。因此，我们进行了这项研究，以探讨谷氨酸能信号是否在DSP的发展中起作用。方法沙哌啶醇（0.75 mg/kg/d，连续14 d）或对照物经渗透微型泵灌胃给药。根据运动数据将氟哌啶醇处理大鼠分为DSP大鼠组和非DSP大鼠组。检测大鼠脑组织中谷氨酸、谷氨酰胺、甘氨酸、l-丝氨酸、d -丝氨酸和GABA的水平以及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。结果在DSP大鼠中，GABA /谷氨酸比值显著升高。此外，l -丝氨酸与甘氨酸的比值也有所提高。DSP大鼠纹状体GAD和SHMT2的表达显著升高。非dsp大鼠纹状体NMDAR2B表达明显降低。结论本研究提示DSP大鼠谷氨酸能信号相对减少为GABA。过量氟哌啶醇可诱导非dsp大鼠纹状体NMDAR功能减退，可防止迟发性运动障碍的形成，但会引起治疗抵抗。鉴于需要治疗难治性精神分裂症的策略，进一步的研究探索我们目前的发现是必要的。
BackgroundThe 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.MethodsHaloperidol (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.ResultsIn 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.ConclusionsThe 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.