Rodnyy Alexander Ya, Kondaurova Elena M, Bazovkina Darya V, Kulikova Elisabeth A, Ilchibaeva Tatiana V, Kovetskaya Alexandra I, Baraboshkina Irina A, Bazhenova Ekaterina Yu, Popova Nina K, Naumenko Vladimir S
Federal Research Center Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Science, Novosibirsk, Russia.
J Neurosci Res. 2022 Jul;100(7):1506-1523. doi: 10.1002/jnr.25055. Epub 2022 Apr 20.
Heterodimerization between 5-HT and 5-HT receptors seems to play an important role in the mechanism of depression and antidepressant drug action. It was suggested that the shift of the ratio between 5-HT /5-HT hetero- and 5-HT /5-HT homodimers in presynaptic neurons toward 5-HT /5-HT homodimers is one of the reasons of depression. Consequently, the artificial elevation of 5-HT receptor number in presynaptic terminals might restore physiological homo-/heterodimer ratio resulting in antidepressive effect. Here we showed that adeno-associated virus (AAV)-based 5-HT receptor overexpression in the midbrain raphe nuclei area produced antidepressive effect in male mice of both C57Bl/6J and genetically predisposed to depressive-like behavior ASC (antidepressant sensitive cataleptics) strains. These changes were accompanied by the elevation of 5-HT receptor mRNA level in the frontal cortex of C57Bl/6J and its reduction in the hippocampus of ASC mice. The presence of engineered 5-HT receptor in the midbrain of both mouse strains was further demonstrated. Importantly that 5-HT receptor overexpression resulted in the reduction of 5-HT receptor level in the membrane protein fraction from the midbrain samples of C57Bl/6J, but not ASC, mice. 5-HT receptor overexpression caused an increase of 5-HIAA/5-HT ratio in the midbrain and the frontal cortex of C57Bl/6J and in all investigated brain structures of ASC mice. Thus, 5-HT receptor overexpression in the raphe nuclei area affects brain 5-HT system and causes antidepressive effect both in C57Bl/6J and in "depressive" ASC male mice. Obtained results indicate the involvement of 5-HT receptor in the mechanisms underlying depressive behavior.
5-羟色胺（5-HT）与5-HT受体之间的异源二聚化似乎在抑郁症机制及抗抑郁药物作用中发挥重要作用。有研究表明，突触前神经元中5-HT /5-HT异源二聚体与5-HT /5-HT同源二聚体的比例向5-HT /5-HT同源二聚体转变是抑郁症的原因之一。因此，人工提高突触前终末5-HT受体数量可能会恢复生理上的同源/异源二聚体比例，从而产生抗抑郁作用。在此我们表明，基于腺相关病毒（AAV）的5-HT受体在中脑缝际核区域过表达，在C57Bl/6J雄性小鼠以及具有抑郁样行为遗传易感性的ASC（抗抑郁药敏感僵住症）品系雄性小鼠中均产生了抗抑郁作用。这些变化伴随着C57Bl/6J小鼠额叶皮质中5-HT受体mRNA水平的升高以及ASC小鼠海马体中该水平的降低。进一步证实了两种小鼠品系的中脑均存在工程化的5-HT受体。重要的是，5-HT受体过表达导致C57Bl/6J小鼠而非ASC小鼠中脑样本膜蛋白部分的5-HT受体水平降低。5-HT受体过表达使C57Bl/6J小鼠中脑和额叶皮质以及ASC小鼠所有研究脑区的5-羟吲哚乙酸（5-HIAA）/5-HT比值升高。因此，缝际核区域的5-HT受体过表达会影响大脑5-HT系统，并在C57Bl/6J和“抑郁型”ASC雄性小鼠中均产生抗抑郁作用。所得结果表明5-HT受体参与了抑郁行为的潜在机制。
