Schizophrenia is a psychotic disorder with an increasing prevalence and incidence over the last two decades. The condition presents with a diverse array of positive, negative, and cognitive impairments. Conventional treatments often yield unsatisfactory outcomes, especially with negative symptoms. We investigated the role of prefrontocortical (PFC) N‐methyl‐D‐aspartate receptors (NMDARs) in the pathophysiology and development of schizophrenia. We explored the potential therapeutic effects of cannabidiolic acid (CBDA) methyl ester (HU‐580), an analogue of CBDA known to act as an agonist of the serotonin‐1A receptor (5‐HT1AR) and an antagonist of cannabinoid type 1 receptor (CB1R). C57BL/6 mice were intraperitoneally administered the NMDAR antagonist, dizocilpine (MK‐801, .3 mg/kg) once daily for 17 days. After 7 days, they were concurrently given HU‐580 (.01 or .05 μg/kg) for 10 days. Behavioural deficits were assessed at two time points. We conducted enzyme‐linked immunosorbent assays to measure the concentration of PFC 5‐HT1AR and CB1R. We found that MK‐801 effectively induced schizophrenia‐related behaviours including hyperactivity, social withdrawal, increased forced swim immobility, and cognitive deficits. We discovered that low‐dose HU‐580 (.01 μg/kg), but not the high dose (.05 μg/kg), attenuated hyperactivity, forced swim immobility and cognitive deficits, particularly in female mice. Our results revealed that MK‐801 downregulated both CB1R and 5‐HT1AR, an effect that was blocked by both low‐ and high‐dose HU‐580. This study sheds light on the potential antipsychotic properties of HU‐580, particularly in the context of NMDAR‐induced dysfunction. Our findings could contribute significantly to our understanding of schizophrenia pathophysiology and offer a promising avenue for exploring the therapeutic potential of HU‐580 and related compounds in alleviating symptoms.

中文翻译：

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大麻二酚酸甲酯在 MK-801 精神分裂症小鼠模型中的治疗样活性：大麻素 CB1 和 5-羟色胺-1A 受体的作用

精神分裂症是一种精神障碍，在过去二十年中患病率和发病率不断增加。该病症表现为多种积极、消极和认知障碍。传统治疗常常产生不令人满意的结果，尤其是在出现阴性症状时。我们研究了前额皮质 (PFC) N-甲基-D-天冬氨酸受体 (NMDAR) 在精神分裂症的病理生理学和发展中的作用。我们探索了大麻二酚酸 (CBDA) 甲酯 (HU-580) 的潜在治疗作用，CBDA 是一种 CBDA 类似物，已知可作为 5-羟色胺-1A 受体 (5-HT1AR) 的激动剂和大麻素 1 型受体的拮抗剂（ CB1R）。C57BL/6 小鼠腹腔注射 NMDAR 拮抗剂地佐环平（MK-801，0.3 mg/kg），每天一次，持续 17 天。7 天后，他们同时给予 HU-580（0.01 或 0.05 μg/kg）10 天。在两个时间点评估行为缺陷。我们进行了酶联免疫吸附测定来测量 PFC 5-HT1AR 和 CB1R 的浓度。我们发现 MK-801 有效诱导精神分裂症相关行为，包括多动、社交退缩、强迫游泳不动和认知缺陷。我们发现低剂量 HU-580（0.01 μg/kg）而非高剂量（0.05 μg/kg）可以减轻多动症、强迫游泳不动和认知缺陷，特别是在雌性小鼠中。我们的结果显示，MK-801 下调 CB1R 和 5-HT1AR，这种作用被低剂量和高剂量 HU-580 阻断。这项研究揭示了 HU-580 的潜在抗精神病特性，特别是在 NMDAR 引起的功能障碍的情况下。我们的研究结果可以极大地促进我们对精神分裂症病理生理学的理解，并为探索 HU-580 和相关化合物在缓解症状方面的治疗潜力提供一个有前景的途径。