Department of Neuroscience, Karolinska Institutet, Biomedicum, Lab B0851, Solnavägen 9, 17 177 Stockholm, Sweden.
Department of Biomolecular Science, Section of Morphology, Physiology and Environmental Biology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca' le Suore 2, I-61029 Urbino, Italy.
Int J Mol Sci. 2021 Feb 15;22(4):1927. doi: 10.3390/ijms22041927.
Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor-receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor-receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor-receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.
血清素通讯主要在细胞外空间和脑脊液（CSF）中运行，使用体积传递，血清素通过能量梯度从源细胞到靶细胞（神经元和星形胶质细胞）移动，导致血清素的扩散和对流（流动）。抑郁症的一个新兴概念是，高度脆弱的 5-HT1A 异源受体复合物中的整合变构受体-受体相互作用的干扰可能导致重度抑郁症的发生，并成为治疗重度抑郁症（MD）和焦虑症的新靶点。例如，中缝核-海马 5-HT 神经元系统中 5-HT1A-FGFR1 异源受体复合物的破坏和/或功能障碍可能导致 MD 的发生。这导致中缝皮质和中缝纹状体 5-HT 通路以及所有前脑网络中的神经可塑性降低和潜在萎缩。通过激动剂激活 5-HT1A-FGFR1 异源复合物中的变构受体-受体相互作用，中脑 5-HT 神经元中的 5-HT1A 自身受体功能降低、可塑性增加和营养活性增加。此外，5-HT1AR-5-HT2AR 同型受体复合物中的抑制性变构受体-受体相互作用可能在调节情绪方面发挥重要作用，涉及到 5-HT2AR 原体激活时前脑 5-HT1AR 原体信号的减少。此外，催产素受体（OXTRs）在调节社交和认知相关行为（如联系和依恋、奖励和动机）方面发挥着重要而令人印象深刻的作用。5-HT2AR 和特别是 5-HT2CR 异源受体复合物中 OXTR 原体的病理性迟钝可能导致抑郁症和其他涉及社交行为障碍的精神疾病的发生。5-HTR 异源复合物是治疗 MD 的新靶点。
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