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One emerging concept in depression is that disturbances in the integrative allosteric receptor\u2013receptor 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\u2013receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor\u2013receptor 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.<\/jats:p>","DOI":"10.3390\/ijms22041927","type":"journal-article","created":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T22:58:01Z","timestamp":1613429881000},"page":"1927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":108,"title":["The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5736-373X","authenticated-orcid":false,"given":"Dasiel O.","family":"Borroto-Escuela","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum, Lab B0851, Solnav\u00e4gen 9, 17 177 Stockholm, Sweden"},{"name":"Department of Biomolecular Science, Section of Morphology, Physiology and Environmental Biology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca\u2019 le Suore 2, I-61029 Urbino, Italy"},{"name":"Observatorio Cubano de Neurociencias, Grupo Boh\u00edo-Estudio, Zayas 50, 62100 Yaguajay, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3195-0725","authenticated-orcid":false,"given":"Patrizia","family":"Ambrogini","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Science, Section of Morphology, Physiology and Environmental Biology, University of Urbino, Campus Scientifico Enrico Mattei, via Ca\u2019 le Suore 2, I-61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Chru\u015bcicka","sequence":"additional","affiliation":[{"name":"APC Microbiome Ireland, University College Cork, T12K8AF Cork, Ireland"},{"name":"Ma\u0142opolska Centre of Biotechnology, Jagiellonian University, 30 252 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lindskog","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Uppsala, 75 105 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minerva","family":"Crespo-Ramirez","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Hern\u00e1ndez-Mondrag\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Perez de la Mora","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 04510, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-3797","authenticated-orcid":false,"given":"Harri\u00ebt","family":"Schellekens","sequence":"additional","affiliation":[{"name":"APC Microbiome Ireland, University College Cork, T12K8AF Cork, Ireland"},{"name":"Department of Anatomy and Neuroscience, University College Cork, T12K8AF Cork, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8491-4288","authenticated-orcid":false,"given":"Kjell","family":"Fuxe","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, Biomedicum, Lab B0851, Solnav\u00e4gen 9, 17 177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"ref_1","first-page":"237","article-title":"Evidence for the Existence of Monoamine Neurons in the Central Nervous System. 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