Schizophrenia (SCZ) has been associated with serotonergic and endocannabinoid systems dysregulation, but difficulty in obtaining in vivo neurological tissue has limited its exploration. We investigated CB₁R-5-HT_2AR heteromer expression and functionality via intracellular pERK and cAMP quantification in olfactory neuroepithelium (ON) cells of SCZ patients non-cannabis users (SCZ/nc), and evaluated whether cannabis modulated these parameters in patients using cannabis (SCZ/c). Results were compared vs healthy controls non-cannabis users (HC/nc) and healthy controls cannabis users (HC/c). Further, antipsychotic effects on heteromer signaling were tested in vitro in HC/nc and HC/c. Results indicated that heteromer expression was enhanced in both SCZ groups vs HC/nc. Additionally, pooling all 4 groups together, heteromer expression correlated with worse attentional performance and more neurological soft signs (NSS), indicating that these changes may be useful markers for neurocognitive impairment. Remarkably, the previously reported signaling properties of CB₁R-5-HT_2AR heteromers in ON cells were absent, specifically in SCZ/nc treated with clozapine. These findings were mimicked in cells from HC/nc exposed to clozapine, suggesting a major role of this antipsychotic in altering the quaternary structure of the CB₁R-5-HT_2AR heteromer in SCZ/nc patients. In contrast, cells from SCZ/c showed enhanced heteromer functionality similar to HC/c. Our data highlight a molecular marker of the interaction between antipsychotic medication and cannabis use in SCZ with relevance for future studies evaluating its association with specific neuropsychiatric alterations.

中文翻译：

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大麻使用调节精神分裂症患者嗅觉神经上皮细胞中 CB1R-5-HT2AR 异聚体中的信号改变

精神分裂症 (SCZ) 与血清素能和内源性大麻素系统失调有关，但难以获得体内神经组织限制了其探索。我们研究了 CB ₁ R-5-HT _2A通过细胞内 pERK 和 cAMP 量化 SCZ 患者非大麻使用者 (SCZ/nc) 的嗅觉神经上皮 (ON) 细胞中的 R 异聚体表达和功能，并评估大麻是否在使用大麻的患者中调节这些参数 (SCZ/c)。结果与健康对照非大麻使用者 (HC/nc) 和健康对照大麻使用者 (HC/c) 进行了比较。此外，在 HC/nc 和 HC/c 中体外测试了对异聚体信号传导的抗精神病作用。结果表明，与 HC/nc 相比，两个 SCZ 组的异聚体表达均增强。此外，将所有 4 组合并在一起，异聚体表达与较差的注意力表现和更多的神经软体征 (NSS) 相关，表明这些变化可能是神经认知障碍的有用标志物。值得注意的是，先前报道的 CB 的信号特性₁ R-5-HT _2A R 异聚体在 ON 细胞中不存在，特别是在用氯氮平处理的 SCZ/nc 中。这些发现在暴露于氯氮平的 HC/nc 细胞中得到了模拟，表明这种抗精神病药在改变SCZ/nc 患者中CB ₁ R-5-HT _2AR R 异聚体的四级结构中的主要作用。相比之下，来自 SCZ/c 的细胞显示出类似于 HC/c 的增强的异聚体功能。我们的数据突出了 SCZ 中抗精神病药物和大麻使用之间相互作用的分子标记，与未来研究评估其与特定神经精神病学改变的关联具有相关性。