Preclinical findings in rodent models pointed toward activation of metabotropic glutamate 2/3 (mGlu2/3) receptors as a new pharmacological approach to treat psychosis. However, more recent studies failed to show clinical efficacy of mGlu2/3 receptor agonism in schizophrenia patients. We previously proposed that long-term antipsychotic medication restricted the therapeutic effects of these glutamatergic agents. However, little is known about the molecular mechanism underlying the potential repercussion of previous antipsychotic exposure on the therapeutic performance of mGlu2/3 receptor agonists. Here we show that this maladaptive effect of antipsychotic treatment is mediated mostly via histone deacetylase 2 (HDAC2). Chronic treatment with the antipsychotic clozapine led to a decrease in mouse frontal cortex mGlu2 mRNA, an effect that required expression of both HDAC2 and the serotonin 5-HT2A receptor. This transcriptional alteration occurred in association with HDAC2-dependent repressive histone modifications at the mGlu2 promoter. We found that chronic clozapine treatment decreased via HDAC2 the capabilities of the mGlu2/3 receptor agonist LY379268 to activate G-proteins in the frontal cortex of mice. Chronic clozapine treatment blunted the antipsychotic-related behavioral effects of LY379268, an effect that was not observed in HDAC2 knockout mice. More importantly, co-administration of the class I and II HDAC inhibitor SAHA (vorinostat) preserved the antipsychotic profile of LY379268 and frontal cortex mGlu2/3 receptor density in wild-type mice. These findings raise concerns on the design of previous clinical studies with mGlu2/3 agonists, providing the rationale for the development of HDAC2 inhibitors as a new epigenetic-based approach to improve the currently limited response to treatment with glutamatergic antipsychotics.

中文翻译：

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慢性氯氮平治疗通过 HDAC2 抑制 mGlu2 受体激动剂在抗精神病活性啮齿动物模型中的表现。

啮齿动物模型的临床前研究结果表明，代谢型谷氨酸 2/3 (mGlu2/3) 受体的激活是一种治疗精神病的新药理学方法。然而，最近的研究未能显示 mGlu2/3 受体激动剂在精神分裂症患者中的临床疗效。我们之前提出长期抗精神病药物限制了这些谷氨酸能药物的治疗效果。然而，关于先前抗精神病药物暴露对 mGlu2/3 受体激动剂治疗性能的潜在影响的分子机制知之甚少。在这里，我们表明抗精神病药物治疗的这种适应不良作用主要是通过组蛋白脱乙酰酶 2 (HDAC2) 介导的。用抗精神病药氯氮平长期治疗导致小鼠额叶皮层 mGlu2 mRNA 减少，需要表达 HDAC2 和血清素 5-HT2A 受体的效果。这种转录改变与 mGlu2 启动子的 HDAC2 依赖性抑制性组蛋白修饰有关。我们发现慢性氯氮平治疗通过 HDAC2 降低了 mGlu2/3 受体激动剂 LY379268 激活小鼠额叶皮层 G 蛋白的能力。慢性氯氮平治疗减弱了 LY379268 的抗精神病药物相关行为效应，这种效应在 HDAC2 敲除小鼠中未观察到。更重要的是，I 类和 II 类 HDAC 抑制剂 SAHA（伏立诺他）的共同给药保留了野生型小鼠 LY379268 和额叶皮层 mGlu2/3 受体密度的抗精神病药谱。这些发现引起了人们对先前使用 mGlu2/3 激动剂的临床研究设计的担忧，