Nogueira Margareth, Ferreira Golbert Daiane C, Menezes Richardson, Nóbrega de Almeida Raíssa, Galvão-Coelho Nicole L, Siroky Andressa N, Lima Thiago Z, Maia Helton, Leão Katarina E, Leão Richardson N
Neurodynamics Lab, Brain Institute, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
Hearing and Neuronal Activity Lab, Brain Institute, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
Mol Psychiatry. 2025 Jan;30(1):50-60. doi: 10.1038/s41380-024-02655-w. Epub 2024 Jul 5.
Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. However, a comprehensive mechanism of action is still lacking. Here, we investigated how a single dose of the short-acting 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) acts on gene expression from microdissected brain regions (anterior cingulate cortex - ACC; basolateral amygdala - BLA; ventral hippocampus CA1 region - vCA1 and dentate gyrus-DG) of naive and stressed mice. Specifically, we compared gene expression of Arc, Zif268, BDNF, CREB, mTORC1, NR2A, TRIP8b, and NFkB in mice injected with 5-MeO-DMT or saline at different time points (1 h, 5 h, or 5 days prior). 5-MeO-DMT altered mRNA expression of immediate early genes Arc and ZiF268 in the ACC, BLA, and vCA1, while NR2A expression was decreased after 5 h in the vCA1. We also found a long-term increase in TRIP8b, a gene related to the modulation of neuronal activity, in the vCA1 after 5 days. Behaviorally, 5-MeO-DMT treated mice showed mixed anxiolytic and anxiogenic effects in the elevated plus maze and open field test 24 h or 5 days after treatment. However, pre-treated mice subjected to acute stress showed both lower corticosterone levels and robust anxiolytic effects of 5-MeO-DMT administration. Together, our findings provide insights into the molecular actions of 5-MeO-DMT in the brain related to anxiolytic effects of behavior.
血清素能致幻剂在治疗焦虑和情绪障碍方面具有潜在治疗效果，通常在单次给药后即可显现，且被认为具有诱导可塑性的作用。然而，其全面的作用机制仍不明确。在此，我们研究了单次剂量的短效5-甲氧基-N,N-二甲基色胺（5-MeO-DMT）对未受应激和应激小鼠经显微切割的脑区（前扣带回皮质 - ACC；基底外侧杏仁核 - BLA；腹侧海马CA1区 - vCA1和齿状回 - DG）基因表达的影响。具体而言，我们比较了在不同时间点（给药前1小时、5小时或5天）注射5-MeO-DMT或生理盐水的小鼠中Arc、Zif268、BDNF、CREB、mTORC1、NR2A、TRIP8b和NFkB的基因表达。5-MeO-DMT改变了ACC、BLA和vCA1中即早基因Arc和ZiF268的mRNA表达，而vCA1中NR2A的表达在5小时后降低。我们还发现，5天后vCA1中与神经元活动调节相关的基因TRIP8b长期增加。行为学上，5-MeO-DMT处理的小鼠在给药后24小时或5天的高架十字迷宫和旷场试验中表现出抗焦虑和促焦虑的混合效应。然而，预先处理并遭受急性应激的小鼠，其皮质酮水平较低，且5-MeO-DMT给药具有显著的抗焦虑作用。总之，我们的研究结果为5-MeO-DMT在大脑中的分子作用提供了见解，这些作用与行为的抗焦虑效应相关。
