Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ⁹-tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.

中文翻译：

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慢性大麻通过 Akt/mTOR 途径促进 5-HT2A 受体的促致幻信号传导。

青春期期间长期使用强效大麻会增加以后患精神分裂症的风险，但迄今为止，所涉及的机制仍不清楚。多项研究结果表明，血清素 2A 受体 (5-HT2AR) 通过抑制性 G 蛋白的功能选择性参与了导致精神病症状的分子机制。此外，该受体在精神分裂症患者的额叶皮层中失调。在这种情况下，涉及大麻暴露和 5-HT2AR 的研究很少。^{在这里，我们在小鼠中测试了早期慢性 Δ 9} -四氢大麻酚 (THC) 暴露对皮质 5-HT2AR 表达及其体内和体外功能的影响。长期接触 THC 会诱导 5-HT2AR 产生致幻性分子构象，并加剧精神分裂症样反应，例如前脉冲抑制破坏。长期接触 THC 后，观察到 5-HT2AR 与抑制性 Gαi1-、Gαi3-、Gαo- 和 Gαz-蛋白的超灵敏偶联，而经典 Gαq/11-蛋白途径没有变化。此外，我们发现雷帕霉素对 Akt/mTOR 通路的抑制可阻断 5-HT2AR 信号传导模式的变化以及对慢性 THC 诱导的精神分裂症样作用的超敏感性。本研究为早年长期接触大麻与成年后发生类似精神病行为的风险增加之间的关系提供了第一个机械解释证据。