RT Journal Article
T1 The role of central serotonin neurons and 5-ht heteroreceptor complexes in the pathophysiology of depression: A historical perspective and future prospects
A1 Borroto-Escuela, Dasiel O.
A1 Ambrogini, Patrizia
A1 Chruścicka, Barbara
A1 Lindskog, Maria
A1 Crespo-Ramirez, Minerva
A1 Hernández-Mondragón, Juan C.
A1 Perez de la Mora, Miguel
A1 Schellekens, Harriët
A1 Fuxe, Kjell
K1 Depresión
K1 Serotonina - Receptores
AB 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, in-creased 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. Addi-tionally, the inhibitory allosteric receptor–receptor interactions in the 5-HT1AR-5-HT2AR isorecep-tor 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 pro-tomer. 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.
PB MDPI
SN 16616596
YR 2021
FD 2021-02-15
LK https://hdl.handle.net/10630/45007
UL https://hdl.handle.net/10630/45007
LA eng
NO Borroto-Escuela, D.O.; Ambrogini, P.; Chruścicka, B.; Lindskog, M.; Crespo-Ramirez, M.; Hernández-Mondragón, J.C.; Perez de la Mora, M.; Schellekens, H.; Fuxe, K. The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects. Int. J. Mol. Sci. 2021, 22, 1927. https://doi.org/10.3390/ijms22041927
NO Swedish Medical Research Council
NO Stiftelsen Olle Engkvist Byggmästare
NO Hjärnfonden
NO Karolinska Institutet Forskningsstiftelser
NO DGAPA–UNAM (PAPIIT), Universidad Nacional Autónoma de México
NO NCN (Narodowe Centrum Nauki, Poland)
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 3 mar 2026