Recently, a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid and sustained antipsychotic effect in treatment-resistant schizophrenia (TRS). Moreover, a single i.p. injection of SNP in rats was found to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in the medial prefrontal cortex (mPFC) brain slices. Here we used the conditioned avoidance response (CAR) test in rats to investigate the antipsychotic-like efficacy of SNP in combination with low-dose risperidone. In addition, we performed microdialysis experiments in freely moving rats to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc). Risperidone caused only 20% suppression of CAR, which is far below the degree of CAR suppression required to predict a significant clinical antipsychotic effect. Addition of a low dose of SNP to risperidone dramatically enhanced the antipsychotic-like effect to a clinically relevant level. SNP significantly enhanced the risperidone-induced dopamine output in the mPFC but not in the NAc. The increased prefrontal dopamine release induced by the drug combination may also improve cognition as indicated by previous preclinical and clinical studies and, furthermore, via enhanced synaptic spine function and morphology in mPFC generate a both rapid and prolonged antipsychotic and pro-cognitive effect. Our results delineate SNP as a promising new treatment option for schizophrenia, including TRS, when added to currently available antipsychotic medication in order to improve efficacy at maintained or even reduced dosage.

中文翻译：

---

硝普钠增强利培酮对大鼠的抗精神病作用

最近，发现单次注射一氧化氮供体硝普钠 (SNP) 可在难治性精神分裂症 (TRS) 中诱导快速且持续的抗精神病作用。此外，发现在大鼠中单次 ip 注射 SNP 会产生大脑突触可塑性的快速和持续变化，包括增强的兴奋性突触后电流反应和内侧前额叶皮层 (mPFC) 脑切片中 V 层锥体细胞的脊柱形态。在这里，我们在大鼠中使用条件回避反应 (CAR) 测试来研究 SNP 与低剂量利培酮组合的抗精神病药功效。此外，我们在自由移动的大鼠中进行了微透析实验，以测量 mPFC 和伏隔核 (NAc) 中的神经递质流出。利培酮仅导致 20% 的 CAR 抑制，这远低于预测显着临床抗精神病作用所需的 CAR 抑制程度。向利培酮添加低剂量的 SNP 可将抗精神病药样作用显着增强至临床相关水平。SNP 在 mPFC 中显着增强了利培酮诱导的多巴胺输出，但在 NAc 中则没有。药物组合诱导的前额叶多巴胺释放增加也可能改善认知，如先前的临床前和临床研究所示，此外，通过增强 mPFC 中的突触脊柱功能和形态，产生快速和持久的抗精神病和促认知作用。我们的结果将 SNP 描述为精神分裂症的一种有前景的新治疗选择，包括 TRS、