{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T03:09:19Z","timestamp":1789787359262,"version":"4.0.1"},"reference-count":111,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T00:00:00Z","timestamp":1627344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004200","name":"Stiftelsen Olle Engkvist Byggm\u00e4stare","doi-asserted-by":"publisher","award":["Fuxe 2019"],"award-info":[{"award-number":["Fuxe 2019"]}],"id":[{"id":"10.13039\/501100004200","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["62X-00715-50-3"],"award-info":[{"award-number":["62X-00715-50-3"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["F02018-0286"],"award-info":[{"award-number":["F02018-0286"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","award":["F02019-0296"],"award-info":[{"award-number":["F02019-0296"]}],"id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Karolinska Institutet Forskningsstiftelser","award":["Borroto-Escuela 2020"],"award-info":[{"award-number":["Borroto-Escuela 2020"]}]},{"name":"EMERGIA","award":["EMERGIA20-39318"],"award-info":[{"award-number":["EMERGIA20-39318"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor\u2013receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1\u201315), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor\u2013receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.<\/jats:p>","DOI":"10.3390\/cells10081902","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T12:18:31Z","timestamp":1627388311000},"page":"1902","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia\u2014Relevance for Mental Diseases"],"prefix":"10.3390","volume":"10","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, 171 77 Stockholm, Sweden"},{"name":"Department of Biomolecular Science Section of Morphology, Physiology and Environmental Biology, Campus Scientifico Enrico Mattei, via Ca\u2019 le Suore 2, 61029 Urbino, Italy"},{"name":"Facultad de Medicina, Instituto de Investigacion de M\u00e1laga, Universidad de Malaga, Campus de Teatinos s\/n, 29071 M\u00e1laga, Spain"}],"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, Campus Scientifico Enrico Mattei, via Ca\u2019 le Suore 2, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0922-4900","authenticated-orcid":false,"given":"Manuel","family":"Narvaez","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Instituto de Investigacion de M\u00e1laga, Universidad de Malaga, Campus de Teatinos s\/n, 29071 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Di Liberto","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Beggiato","sequence":"additional","affiliation":[{"name":"Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-6414","authenticated-orcid":false,"given":"Luca","family":"Ferraro","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology and LTTA Center, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Fores-Pons","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Facultad de Medicina, Instituto de Investigacion de M\u00e1laga, Universidad de Malaga, Campus de Teatinos s\/n, 29071 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose E.","family":"Alvarez-Contino","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Department of Education, School of Medicine, Villa Clara University of Medical Sciences, Polyclinic Juan Bruno Zayas, 52900 Cifuentes, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Lopez-Salas","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Facultad de Medicina, Instituto de Investigacion de M\u00e1laga, Universidad de Malaga, Campus de Teatinos s\/n, 29071 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3275-9981","authenticated-orcid":false,"given":"Giuseppa","family":"Mud\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaida","family":"D\u00edaz-Cabiale","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Instituto de Investigacion de M\u00e1laga, Universidad de Malaga, Campus de Teatinos s\/n, 29071 M\u00e1laga, Spain"}],"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, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3389\/fnmol.2019.00230","article-title":"Oligomeric Receptor Complexes and Their Allosteric Receptor-Receptor Interactions in the Plasma Membrane Represent a New Biological Principle for Integration of Signals in the CNS","volume":"12","author":"Fuxe","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Borroto-Escuela, D.O., Narvaez, M., Ambrogini, P., Ferraro, L., Brito, I., Romero-Fernandez, W., Andrade-Talavera, Y., Flores-Burgess, A., Mill\u00f3n, C., and Gago, B. (2018). Receptor\u2013Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment. Molecules, 23.","DOI":"10.3390\/molecules23061341"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Borroto-Escuela, D., Ambrogini, P., Chru\u015bcicka, B., Lindskog, M., Crespo-Ramirez, M., Hern\u00e1ndez-Mondrag\u00f3n, J., de la Mora, M.P., Schellekens, H., and Fuxe, K. (2021). 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., 22.","DOI":"10.3390\/ijms22041927"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.pharmthera.2012.09.006","article-title":"Serotonin receptors involved in antidepressant effects","volume":"137","author":"Artigas","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.euroneuro.2013.04.013","article-title":"Developments in the field of antidepressants, where do we go now?","volume":"25","author":"Artigas","year":"2015","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.tins.2015.11.003","article-title":"FGFR1\u20135-HT1A Heteroreceptor Complexes: Implications for Understanding and Treating Major Depression","volume":"39","author":"Tarakanov","year":"2016","journal-title":"Trends Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3389\/fncel.2017.00309","article-title":"Disturbances in the FGFR1-5-HT1A Heteroreceptor Complexes in the Raphe-Hippocampal 5-HT System Develop in a Genetic Rat Model of Depression","volume":"11","author":"Dupont","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1007\/s00429-015-1180-y","article-title":"Galanin (1\u201315) enhances the antidepressant effects of the 5-HT1A receptor agonist 8-OH-DPAT: Involvement of the raphe-hippocampal 5-HT neuron system","volume":"221","author":"Santin","year":"2016","journal-title":"Brain Struct. Funct."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.npep.2017.01.004","article-title":"The neuropeptides Galanin and Galanin(1\u201315) in depression-like behaviours","volume":"64","author":"Flores","year":"2017","journal-title":"Neuropeptides"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fendo.2012.00127","article-title":"On the existence and function of galanin receptor heteromers in the central nervous system","volume":"3","author":"Fuxe","year":"2012","journal-title":"Front. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.bbrc.2010.09.110","article-title":"Dopamine D2 and 5-hydroxytryptamine 5-HT2A receptors assemble into functionally interacting heteromers","volume":"401","author":"Tarakanov","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","first-page":"1347","article-title":"Hetero-dimerization of serotonin 5-HT2A and dopamine D2 receptors","volume":"1803","author":"Polit","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Bioenerg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107914","DOI":"10.1016\/j.neuropharm.2019.107914","article-title":"Astrocyte control of glutamatergic activity: Downstream effects on serotonergic function and emotional behavior","volume":"166","author":"Fullana","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/jnc.13885","article-title":"A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes","volume":"140","author":"Cervetto","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108070","DOI":"10.1016\/j.neuropharm.2020.108070","article-title":"Existence of FGFR1-5-HT1AR heteroreceptor complexes in hippocampal astrocytes. Putative link to 5-HT and FGF2 modulation of hippocampal gamma oscillations","volume":"170","author":"Fredriksson","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2019.07.046","article-title":"Oxytocin and Stress: Neural Mechanisms, Stress-Related Disorders, and Therapeutic Approaches","volume":"417","author":"Matsushita","year":"2019","journal-title":"Neuroscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5354","DOI":"10.1021\/ac049295f","article-title":"Combining Mass Spectrometry and Pull-Down Techniques for the Study of Receptor Heteromerization. Direct Epitope\u2212Epitope Electrostatic Interactions between Adenosine A2Aand Dopamine D2Receptors","volume":"76","author":"Ciruela","year":"2004","journal-title":"Anal. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1476-5381.1968.tb07943.x","article-title":"Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide","volume":"34","author":"Corrodi","year":"1968","journal-title":"Br. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0014-2999(76)90304-6","article-title":"The effect of mepiprazole on central monoamine neurons. Evidence for increased 5-hydroxytryptamine and dopamine receptor activity","volume":"35","author":"Fuxe","year":"1976","journal-title":"Eur. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1538\/expanim.59.441","article-title":"Hallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Senescence-Accelerated Mice","volume":"59","author":"Niimi","year":"2010","journal-title":"Exp. Anim."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.bbrc.2013.11.104","article-title":"Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes","volume":"443","author":"Narvaez","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1177\/2045125316637570","article-title":"Multiple D2 heteroreceptor complexes: New targets for treatment of schizophrenia","volume":"6","author":"Pintsuk","year":"2016","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/sj.mp.4001556","article-title":"Treatments for schizophrenia: A critical review of pharmacology and mechanisms of action of antipsychotic drugs","volume":"10","author":"Miyamoto","year":"2004","journal-title":"Mol. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.2174\/138920112800784880","article-title":"Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia","volume":"13","author":"Meltzer","year":"2012","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.coph.2016.10.004","article-title":"Diversity and bias through dopamine D2R heteroreceptor complexes","volume":"32","author":"Fuxe","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Borroto-Escuela, D.O., Ferraro, L., Narvaez, M., Tanganelli, S., Beggiato, S., Liu, F., Rivera, A., and Fuxe, K. (2020). Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia. Cells, 9.","DOI":"10.3390\/cells9051077"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1038\/sj.npp.1301324","article-title":"The Effects of the Preferential 5-HT2A Agonist Psilocybin on Prepulse Inhibition of Startle in Healthy Human Volunteers Depend on Interstimulus Interval","volume":"32","author":"Vollenweider","year":"2007","journal-title":"Neuropsychopharmacology"},{"key":"ref_28","first-page":"846","article-title":"3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions","volume":"297","author":"Bankson","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1177\/0269881110378371","article-title":"The safety and efficacy of \u00b13,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: The first randomized controlled pilot study","volume":"25","author":"Mithoefer","year":"2010","journal-title":"J. Psychopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1021\/acschemneuro.8b00665","article-title":"Attenuation of Oxytocin and Serotonin 2A Receptor Signaling through Novel Heteroreceptor Formation","volume":"10","author":"Fitzsimons","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1152\/physrev.00031.2017","article-title":"The Oxytocin Receptor: From Intracellular Signaling to Behavior","volume":"98","author":"Jurek","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/jnc.13582","article-title":"Dopamine D2 and serotonin 5-HT1A receptor interaction in the context of the effects of antipsychotics\u2014in vitro studies","volume":"137","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.neuroscience.2018.03.004","article-title":"Paroxetine and Low-dose Risperidone Induce Serotonin 5-HT1A and Dopamine D2 Receptor Heteromerization in the Mouse Prefrontal Cortex","volume":"377","author":"Kolasa","year":"2018","journal-title":"Neuroscience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4779","DOI":"10.1021\/acsomega.7b00629","article-title":"Existence of Brain 5-HT1A\u20135-HT2A Isoreceptor Complexes with Antagonistic Allosteric Receptor\u2013Receptor Interactions Regulating 5-HT1A Receptor Recognition","volume":"2","author":"Li","year":"2017","journal-title":"ACS Omega"},{"key":"ref_35","first-page":"pyu064","article-title":"A Role for Galanin N-Terminal Fragment (1\u201315) in Anxiety- and Depression-Related Behaviors in Rats","volume":"18","author":"Santin","year":"2015","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0014-2999(92)90806-F","article-title":"Evidence for specific N-terminal galanin fragment binding sites in the rat brain","volume":"224","author":"Hedlund","year":"1992","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.bbrc.2014.08.061","article-title":"Preferential activation by galanin 1\u201315 fragment of the GalR1 protomer of a GalR1\u2013GalR2 heteroreceptor complex","volume":"452","author":"Narvaez","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1097\/00001756-200002280-00018","article-title":"Galanin-(1-16) modulates 5-HT1A receptors in the ventral limbic cortex of the rat","volume":"11","author":"Narvaez","year":"2000","journal-title":"Neuroreport"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.regpep.2010.04.014","article-title":"The Galanin N-terminal fragment (1\u201315) interacts with neuropeptide Y in central cardiovascular control: Involvement of the NPY Y2 receptor subtype","volume":"163","author":"Parrado","year":"2010","journal-title":"Regul. Pept."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/0006-8993(94)90271-2","article-title":"Galanin-(1\u201315), but not galanin-(1\u201329), modulates 5-HT1A receptors in the dorsal hippocampus of the rat brain: Possible existence of galanin receptor subtypes","volume":"634","author":"Hedlund","year":"1994","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.neuropharm.2017.03.010","article-title":"Galanin (1-15) enhancement of the behavioral effects of Fluoxetine in the forced swimming test gives a new therapeutic strategy against depression","volume":"118","author":"Gago","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/978-1-4939-8576-0_9","article-title":"Small interference RNA knockdown rats in behavioral functions. GalR1-GalR2 heteroreceptor in anxiety and depression-like behaviour","volume":"Volume 140","author":"Fuxe","year":"2018","journal-title":"Receptor-Receptor Interactions in the Central Nervous System"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.neuropharm.2019.05.023","article-title":"Galanin (1\u201315)-fluoxetine interaction in the novel object recognition test. Involvement of 5-HT1A receptors in the prefrontal cortex of the rats","volume":"155","author":"Gago","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_44","first-page":"37","article-title":"Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease","volume":"11","author":"Carlsson","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1586\/14737175.2014.922878","article-title":"The impact of receptor\u2013receptor interactions in heteroreceptor complexes on brain plasticity","volume":"14","author":"Fuxe","year":"2014","journal-title":"Expert Rev. Neurother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1177\/0269881119844188","article-title":"Role of the galanin N-terminal fragment (1-15) in anhedonia: Involvement of the dopaminergic mesolimbic system","volume":"33","author":"Flores","year":"2019","journal-title":"J. Psychopharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s00702-019-01997-y","article-title":"Dopaminergic modulation of striatal function and Parkinson\u2019s disease","volume":"126","author":"Zhai","year":"2019","journal-title":"J. Neural Transm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s00702-006-0589-0","article-title":"Intramembrane receptor\u2013receptor interactions: A novel principle in molecular medicine","volume":"114","author":"Fuxe","year":"2006","journal-title":"J. Neural Transm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.neuropharm.2018.11.018","article-title":"Crosstalk between receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCR) in the brain: Focus on heteroreceptor complexes and related functional neurotrophic effects","volume":"152","author":"Belluardo","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF01248925","article-title":"Chronic immobilization stress: Evidence for decreases of 5-hydroxy-tryptamine immunoreactivity and for increases of glucocorticoid receptor immunoreactivity in various brain regions of the male rat","volume":"77","author":"Kitayama","year":"1989","journal-title":"J. Neural Transm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"111289","DOI":"10.1016\/j.mad.2020.111289","article-title":"Evidence for the existence of A2AR-TrkB heteroreceptor complexes in the dorsal hippocampus of the rat brain: Potential implications of A2AR and TrkB interplay upon ageing","volume":"190","author":"Sartini","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1038\/nn.2216","article-title":"FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity","volume":"11","author":"Flajolet","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.biopsych.2011.09.012","article-title":"Fibroblast Growth Factor Receptor 1\u2013 5-Hydroxytryptamine 1A Heteroreceptor Complexes and Their Enhancement of Hippocampal Plasticity","volume":"71","author":"Ciruela","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.bbrc.2014.11.112","article-title":"Evidence for the existence of FGFR1\u20135-HT1A heteroreceptor complexes in the midbrain raphe 5-HT system","volume":"456","author":"Narvaez","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.bbrc.2015.04.133","article-title":"Enhancement of the FGFR1 signaling in the FGFR1-5-HT1A heteroreceptor complex in midbrain raphe 5-HT neuron systems. Relevance for neuroplasticity and depression","volume":"463","author":"Narvaez","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/j.cell.2021.01.034","article-title":"Antidepressant drugs act by directly binding to TRKB neurotrophin receptors","volume":"184","author":"Casarotto","year":"2021","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.biopsych.2006.02.013","article-title":"A Neurotrophic Model for Stress-Related Mood Disorders","volume":"59","author":"Duman","year":"2006","journal-title":"Biol. Psychiatry"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1038\/mp.2017.61","article-title":"Neuronal plasticity and neurotrophic factors in drug responses","volume":"22","author":"Antila","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6417","DOI":"10.1523\/JNEUROSCI.0690-07.2007","article-title":"Brain-Derived Neurotrophic Factor Regulates Cholesterol Metabolism for Synapse Development","volume":"27","author":"Suzuki","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"616178","DOI":"10.3389\/fnmol.2021.616178","article-title":"Depletion of TrkB Receptors From Adult Serotonergic Neurons Increases Brain Serotonin Levels, Enhances Energy Metabolism and Impairs Learning and Memory","volume":"14","author":"Sahu","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.neuropharm.2018.03.011","article-title":"Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN","volume":"135","author":"Diniz","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3389\/fnbeh.2014.00391","article-title":"5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation","volume":"8","author":"Samarajeewa","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Rantam\u00e4ki, T., Vesa, L., Antila, H., Di Lieto, A., Tammela, P., Schmitt, A., Lesch, K.-P., Rios, M., and Castr\u00e9n, E. (2011). Antidepressant Drugs Transactivate TrkB Neurotrophin Receptors in the Adult Rodent Brain Independently of BDNF and Monoamine Transporter Blockade. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020567"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/B978-0-12-391862-8.00015-6","article-title":"G Protein\u2013Coupled Receptor Heterodimerization in the Brain","volume":"521","author":"Garriga","year":"2013","journal-title":"Methods Enzymol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.bbagen.2016.10.026","article-title":"Existence of muscarinic acetylcholine receptor (mAChR) and fibroblast growth factor receptor (FGFR) heteroreceptor complexes and their enhancement of neurite outgrowth in neural hippocampal cultures","volume":"1861","author":"Frinchi","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Gen. Subj."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1046\/j.1471-4159.2003.01624.x","article-title":"cAMP-induced differentiation of human neuronal progenitor cells is mediated by nuclear fibroblast growth factor receptor-1 (FGFR1)","volume":"84","author":"Stachowiak","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s00213-011-2279-3","article-title":"Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats","volume":"217","author":"Veena","year":"2011","journal-title":"Psychopharmacology"},{"key":"ref_68","first-page":"1","article-title":"Understanding the Functional Plasticity in Neural Networks of the Basal Ganglia in Cocaine Use Disorder: A Role for Allosteric Receptor-Receptor Interactions in A2A-D2 Heteroreceptor Complexes","volume":"2016","author":"Wydra","year":"2016","journal-title":"Neural Plast."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0092-8674(02)00966-2","article-title":"Ligand-Induced, Receptor-Mediated Dimerization and Activation of EGF Receptor","volume":"110","author":"Schlessinger","year":"2002","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/aps.2009.80","article-title":"Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro","volume":"30","author":"Xie","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1111\/j.1471-4159.2005.03055.x","article-title":"Dopamine D2 receptor stimulation of mitogen-activated protein kinases mediated by cell type-dependent transactivation of receptor tyrosine kinases","volume":"93","author":"Wang","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00213-008-1306-5","article-title":"Fluoxetine-mediated 5-HT2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation","volume":"201","author":"Li","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1471-4159.2008.05357.x","article-title":"Serotonin (5-HT) induces glial cell line-derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells","volume":"106","author":"Tsuchioka","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1007\/s11481-013-9479-z","article-title":"The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System","volume":"9","author":"Funa","year":"2013","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Kruk, J.S., Vasefi, M.S., Heikkila, J.J., and Beazely, M.A. (2013). Reactive Oxygen Species Are Required for 5-HT-Induced Transactivation of Neuronal Platelet-Derived Growth Factor and TrkB Receptors, but Not for ERK1\/2 Activation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077027"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.cellsig.2012.09.021","article-title":"5-HT1A receptors transactivate the platelet-derived growth factor receptor type beta in neuronal cells","volume":"25","author":"Kruk","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.mcn.2015.02.013","article-title":"Fluoxetine-induced transactivation of the platelet-derived growth factor type \u03b2 receptor reveals a novel heterologous desensitization process","volume":"65","author":"Kruk","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/S0896-6273(02)00859-0","article-title":"A D2 Class Dopamine Receptor Transactivates a Receptor Tyrosine Kinase to Inhibit NMDA Receptor Transmission","volume":"35","author":"Kotecha","year":"2002","journal-title":"Neuron"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.neuron.2006.10.011","article-title":"Modulation of D2R-NR2B Interactions in Response to Cocaine","volume":"52","author":"Liu","year":"2006","journal-title":"Neuron"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.cell.2016.06.045","article-title":"MDMA as a Probe and Treatment for Social Behaviors","volume":"166","author":"Heifets","year":"2016","journal-title":"Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.neubiorev.2015.08.016","article-title":"The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals","volume":"57","author":"Bedi","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_82","first-page":"891","article-title":"Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine","volume":"41","author":"Preller","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_83","first-page":"236","article-title":"Hallucinogenic drugs of the indolealkylamine type and central monoamine neurons","volume":"179","author":"Corrodi","year":"1971","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"9779","DOI":"10.1073\/pnas.83.24.9779","article-title":"Glucocorticoid receptor immunoreactivity in monoaminergic neurons of rat brain","volume":"83","author":"Harfstrand","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.euroneuro.2013.12.006","article-title":"Psilocybin\u2014Summary of knowledge and new perspectives","volume":"24","author":"Horacek","year":"2014","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e128","DOI":"10.1097\/j.pbj.0000000000000128","article-title":"What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review","volume":"6","author":"Santos","year":"2021","journal-title":"Porto Biomed. J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/mp.2017.255","article-title":"Mechanisms of ketamine action as an antidepressant","volume":"23","author":"Zanos","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1523\/JNEUROSCI.23-01-00349.2003","article-title":"Activation of the TrkB Neurotrophin Receptor Is Induced by Antidepressant Drugs and Is Required for Antidepressant-Induced Behavioral Effects","volume":"23","author":"Saarelainen","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/0166-2236(96)10048-5","article-title":"Calcium signalling in glial cells","volume":"19","author":"Verkhratsky","year":"1996","journal-title":"Trends Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1007\/s11064-015-1574-5","article-title":"Volume Transmission in Central Dopamine and Noradrenaline Neurons and Its Astroglial Targets","volume":"40","author":"Fuxe","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nrn1722","article-title":"Astrocytes, from brain glue to communication elements: The revolution continues","volume":"6","author":"Volterra","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.pneurobio.2009.10.012","article-title":"The discovery of central monoamine neurons gave volume transmission to the wired brain","volume":"90","author":"Fuxe","year":"2010","journal-title":"Prog. Neurobiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.4103\/1673-5374.189168","article-title":"Volume transmission and receptor-receptor interactions in heteroreceptor complexes: Understanding the role of new concepts for brain communication","volume":"11","author":"Fuxe","year":"2016","journal-title":"Neural Regen. Res."},{"key":"ref_94","first-page":"744","article-title":"Glutamate-mediated astrocyte\u2013neuron signalling","volume":"369","author":"Parpura","year":"1994","journal-title":"Nat. Cell Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1126\/science.8134839","article-title":"Direct signaling from astrocytes to neurons in cultures of mammalian brain cells","volume":"263","author":"Nedergaard","year":"1994","journal-title":"Science"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"8629","DOI":"10.1073\/pnas.97.15.8629","article-title":"Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons","volume":"97","author":"Parpura","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1111\/j.1745-7254.2006.00397.x","article-title":"Cellular mechanism for spontaneous calcium oscillations in astrocytes","volume":"27","author":"Wang","year":"2006","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1523\/JNEUROSCI.19-02-00520.1999","article-title":"ATP Released from Astrocytes Mediates Glial Calcium Waves","volume":"19","author":"Guthrie","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4926","DOI":"10.1073\/pnas.97.9.4926","article-title":"D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor","volume":"97","author":"Mothet","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","first-page":"151","article-title":"Growth enhancement effect of BzATP on primary cultured astrocytes from rat brain","volume":"22","author":"Liang","year":"2006","journal-title":"Neurosci. Bull."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/j.1471-4159.2010.07135.x","article-title":"Differential effects of pro- and anti-inflammatory cytokines alone or in combinations on the metabolic profile of astrocytes","volume":"116","author":"Allaman","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nrn.2018.19","article-title":"Lactate in the brain: From metabolic end-product to signalling molecule","volume":"19","author":"Magistretti","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Pelassa, S., Guidolin, D., Venturini, A., Averna, M., Frumento, G., Campanini, L., Bernardi, R., Cortelli, P., Buonaura, G.C., and Maura, G. (2019). A2A-D2 Heteromers on Striatal Astrocytes: Biochemical and Biophysical Evidence. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102457"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e1038","DOI":"10.1038\/tp.2017.7","article-title":"Glial GLT-1 blockade in infralimbic cortex as a new strategy to evoke rapid antidepressant-like effects in rats","volume":"7","author":"Gatius","year":"2017","journal-title":"Transl. Psychiatry"},{"key":"ref_105","first-page":"481","article-title":"NMDAR inhibition-independent antidepressant actions of ketamine metabolites","volume":"533","author":"Zanos","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.euroneuro.2017.10.032","article-title":"Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies","volume":"28","author":"Artigas","year":"2018","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.neuropharm.2018.06.029","article-title":"Serotonergic mechanisms involved in antidepressant-like responses evoked by GLT-1 blockade in rat infralimbic cortex","volume":"139","author":"Gatius","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.euroneuro.2019.09.004","article-title":"In vivo knockdown of astroglial glutamate transporters GLT-1 and GLAST increases excitatory neurotransmission in mouse infralimbic cortex: Relevance for depressive-like phenotypes","volume":"29","author":"Fullana","year":"2019","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1002\/glia.23593","article-title":"Regionally selective knockdown of astroglial glutamate transporters in infralimbic cortex induces a depressive phenotype in mice","volume":"67","author":"Fullana","year":"2019","journal-title":"Glia"},{"key":"ref_110","first-page":"157","article-title":"The nucleus raphe dorsalis of the rat and its projection upon the caudatoputamen. A combined cytoarchitectonic, immunohistochemical and retrograde transport study","volume":"77","author":"Steinbusch","year":"1981","journal-title":"J. Physiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1111\/jnc.13077","article-title":"Early growth response 1 (Egr-1) directly regulates GABAAreceptor \u03b12, \u03b14, and \u03b8 subunits in the hippocampus","volume":"133","author":"Mo","year":"2015","journal-title":"J. Neurochem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/1902\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:35:38Z","timestamp":1760164538000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/8\/1902"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,27]]},"references-count":111,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cells10081902"],"URL":"https:\/\/doi.org\/10.3390\/cells10081902","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,27]]}}}