NMDA receptor blockade in rodents is commonly used to induce schizophrenia-like behavioral abnormalities, including cognitive deficits and social dysfunction. Aberrant glutamate and GABA transmission, particularly in adolescence, is implicated in these behavioral abnormalities. The endocannabinoid system modulates glutamate and GABA transmission, but the impact of endocannabinoid modulation on cognitive and social dysfunction is unclear. Here, we asked whether late-adolescence administration of the anandamide hydrolysis inhibitor URB597 can reverse behavioral deficits induced by early-adolescence administration of the NMDA receptor blocker MK-801. In parallel, we assessed the impact of MK-801 and URB597 on mRNA expression of glutamate and GABA markers. We found that URB597 prevented MK-801-induced novel object recognition deficits and social interaction abnormalities in adult rats, and reversed glutamate and GABA aberrations in the prelimbic PFC. URB597-mediated reversal of MK-801-induced social interaction deficits was mediated by the CB1 receptor, whereas the reversal of cognitive deficits was mediated by the CB2 receptor. This was paralleled by the reversal of CB1 and CB2 receptor expression abnormalities in the basolateral amygdala and prelimbic PFC, respectively. Together, our findings show that interfering with NMDA receptor function in early adolescence has a lasting impact on phenotypes resembling the negative symptoms and cognitive deficits of schizophrenia and on glutamate and GABA marker expression in the PFC. Prevention of behavioral and molecular abnormalities by late-adolescence URB597 via CB1 and CB2 receptors suggests that endocannabinoid stimulation may have therapeutic potential in addressing treatment-resistant symptoms.

中文翻译：

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Anandamide 水解抑制作用可逆转 MK-801 诱导的雄性大鼠的长期行为和基因表达改变：CB1 和 CB2 受体介导的差异效应

啮齿动物中的 NMDA 受体阻断剂通常用于诱发精神分裂症样行为异常，包括认知缺陷和社会功能障碍。异常的谷氨酸和 GABA 传递，尤其是在青春期，与这些行为异常有关。内源性大麻素系统调节谷氨酸和 GABA 传递，但内源性大麻素调节对认知和社会功能障碍的影响尚不清楚。在这里，我们询问了在青春期后期服用 anandamide 水解抑制剂 URB597 是否可以逆转由在青春期早期服用 NMDA 受体阻滞剂 MK-801 引起的行为缺陷。同时，我们评估了 MK-801 和 URB597 对谷氨酸和 GABA 标记物 mRNA 表达的影响。我们发现 URB597 在成年大鼠中阻止了 MK-801 诱导的新物体识别缺陷和社会互动异常，并逆转了前肢前额皮层中的谷氨酸和 GABA 畸变。URB597 介导的 MK-801 诱导的社会互动缺陷的逆转是由 CB1 受体介导的，而认知缺陷的逆转是由 CB2 受体介导的。这与基底外侧杏仁核和前边缘 PFC 中 CB1 和 CB2 受体表达异常的逆转同时发生。总之，我们的研究结果表明，在青春期早期干扰 NMDA 受体功能对类似于精神分裂症的阴性症状和认知缺陷的表型以及 PFC 中的谷氨酸和 GABA 标记物表达具有持久影响。