{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:43:26Z","timestamp":1791420206067,"version":"4.3.3"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010198","name":"Ministerio de Econom\u00eda, Industria y Competitividad, Gobierno de Espa\u00f1a","doi-asserted-by":"publisher","award":["SAF2016-79008-P, PID2020-114392RB-I00"],"award-info":[{"award-number":["SAF2016-79008-P, PID2020-114392RB-I00"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002878","name":"Consejer\u00eda de Econom\u00eda, Innovaci\u00f3n, Ciencia y Empleo, Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["P20_00026, PI-0083-2019 ,UMA18-FEDERJA-008"],"award-info":[{"award-number":["P20_00026, PI-0083-2019 ,UMA18-FEDERJA-008"]}],"id":[{"id":"10.13039\/501100002878","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Selective 5-HT reuptake inhibitor antidepressants (SSRIs) are the first choice in major depressive disorder (MDD), but 50% of affected patients do not show improvement. Galanin(1-15) [GAL(1-15)] enhanced Fluoxetine antidepressant-like effects in an animal model of depression, the olfactory bulbectomy (OBX); however, further detailed analysis of GAL(1-15) effects as augmentation treatment in OBX rats are needed. In OBX rats, we analysed the effect of GAL(1\u201315) on Escitalopram (ESC)-mediated responses in behavioural tests related to despair. We studied whether GAL(1\u201315) effects involved 5-HT1AR using an in vivo model siRNA 5-HT1A knockdown rats. Moreover, we analysed by immunohistochemistry the expression of the immediate-early gene c-Fos (c-Fos IR) after the administration of GAL(1-15)+ESC in OBX rats in several nuclei involved in MDD. GAL(1-15) enhances the antidepressant-like effects of ESC, and the GALR2 antagonist M871 blocked GAL(1-15) mediated actions. The downregulation of 5-HT1AR by siRNA was sufficient to block GAL(1-15) effects. Our immunohistochemistry and principal component analysis (PCA) analysis suggest that two functional networks are involved in these effects; one includes the lateral (LHb) and medial (mHb) habenula, dorsal raphe (DR) and ventral tegmental area (VTA), and the other consists of the dentate gyrus (DG), and prefrontal cortex (PFC). The results open up the possibility of using GAL(1-15) in combination with SSRIs as a novel strategy for treating MDD.<\/jats:p>","DOI":"10.3390\/ijms221910848","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T21:23:55Z","timestamp":1633728235000},"page":"10848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Galanin(1-15) Potentiates the Antidepressant-like Effects Induced by Escitalopram in a Rat Model of Depression"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9345-2457","authenticated-orcid":false,"given":"Laura","family":"Garc\u00eda-Dur\u00e1n","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of Malaga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Flores-Burgess","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of Malaga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelia","family":"Cantero-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of Malaga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Araceli","family":"Puigcerver","sequence":"additional","affiliation":[{"name":"Faculty of Psychology, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of M\u00e1laga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 \u00c1ngel","family":"Narv\u00e1ez","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of Malaga, 29071 Malaga, 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 Institute, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0894-8536","authenticated-orcid":false,"given":"Luis","family":"Sant\u00edn","sequence":"additional","affiliation":[{"name":"Faculty of Psychology, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of M\u00e1laga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-5506","authenticated-orcid":false,"given":"Carmelo","family":"Mill\u00f3n","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of Malaga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4613-9430","authenticated-orcid":false,"given":"Zaida","family":"D\u00edaz-Cabiale","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Research of Malaga, Campus de Teatinos s\/n, University of Malaga, 29071 Malaga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S2215-0366(16)30024-4","article-title":"Scaling-up treatment of depression and anxiety: A global return on investment analysis","volume":"3","author":"Chisholm","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"Malhi","year":"2018","journal-title":"Lancet"},{"key":"ref_3","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_4","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev-publhealth-031912-114409","article-title":"The epidemiology of depression across cultures","volume":"34","author":"Kessler","year":"2013","journal-title":"Annu. Rev. Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"377","DOI":"10.31887\/DCNS.2008.10.4\/mhtrivedi","article-title":"Treatment strategies to improve and sustain remission in major depressive disorder","volume":"10","author":"Trivedi","year":"2008","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jad.2008.10.014","article-title":"What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies","volume":"116","author":"Fekadu","year":"2009","journal-title":"J. Affect. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.brainresrev.2007.11.007","article-title":"Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology","volume":"58","author":"Fuxe","year":"2008","journal-title":"Brain Res. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fuxe, K., Borroto-Escuela, D.O., Romero-Fernandez, W., Tarakanov, A.O., Calvo, F., Garriga, P., Tena, M., Narvaez, M., Mill\u00f3n, C., and Parrado, C. (2012). On the existence and function of galanin receptor heteromers in the central nervous system. Front. Endocrinol., 3.","DOI":"10.3389\/fendo.2012.00127"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0165-6147(00)01446-2","article-title":"Galanin receptor subtypes","volume":"21","author":"Branchek","year":"2000","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1007\/s00018-008-8153-8","article-title":"Galanin, galanin receptors and drug targets","volume":"65","author":"Mitsukawa","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0304-3940(01)02446-6","article-title":"Increased density of galanin binding sites in the dorsal raphe in a genetic rat model of depression","volume":"317","author":"Bellido","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E1666","DOI":"10.1073\/pnas.1403649111","article-title":"Brain galanin system genes interact with life stresses in depression-related phenotypes","volume":"111","author":"Juhasz","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","first-page":"E4726","article-title":"Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray","volume":"113","author":"Wang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10470","DOI":"10.1073\/pnas.0403802101","article-title":"Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests","volume":"101","author":"Bartfai","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1007\/s00018-008-8160-9","article-title":"Galanin, galanin receptor subtypes and depression-like behaviour","volume":"65","author":"Kuteeva","year":"2008","journal-title":"Cell Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.npep.2004.12.012","article-title":"Galanin receptor ligands","volume":"39","author":"Lu","year":"2005","journal-title":"Neuropeptides"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Borroto-Escuela, D.O., Narv\u00e1ez, M., Ambrogini, P., Ferraro, L., Brito, I., Romero-Fernandez, W., Andrade-Talavera, Y., Flores-Burgess, A., Millon, 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_18","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.bbrc.2014.08.061","article-title":"Preferential activation by galanin 1-15 fragment of the GalR1 protomer of a GalR1-GalR2 heteroreceptor complex","volume":"452","author":"Narvaez","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.neuropharm.2011.03.002","article-title":"Galanin receptor\/Neuropeptide Y receptor interactions in the dorsal raphe nucleus of the rat","volume":"61","author":"Parrado","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_20","first-page":"113","article-title":"Neurochemical modulation of central cardiovascular control: The integrative role of galanin","volume":"102","author":"Parrado","year":"2010","journal-title":"Exp. Suppl."},{"key":"ref_21","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":"Gago","year":"2019","journal-title":"J. Psychopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mill\u00f3n, C., Flores-Burgess, A., Narv\u00e1ez, M., Borroto-Escuela, D.O., Sant\u00edn, L., Parrado, C., Narv\u00e1ez, J.A., Fuxe, K., and D\u00edaz-Cabiale, Z. (2014). A role for galanin N-terminal fragment (1\u201315) in anxiety- and depression-related behaviors in rats. Int. J. Neuropsychopharmacol., 18.","DOI":"10.1093\/ijnp\/pyu064"},{"key":"ref_23","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":"Gago","year":"2016","journal-title":"Brain Struct. Funct."},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.neuropharm.2017.03.010","article-title":"Galanin (1\u201315) 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_26","doi-asserted-by":"crossref","unstructured":"Flores-Burgess, A., Mill\u00f3n, C., Gago, B., Garc\u00eda-Dur\u00e1n, L., Cantero-Garc\u00eda, N., Puigcerver, A., Narv\u00e1ez, J., Fuxe, K., Sant\u00edn, L., and D\u00edaz-Cabiale, Z. (2021). Galanin (1\u201315) enhances the behavioral effects of Fluoxetine in the olfatory bulbectomy rat suggesting a new augmentation strategy. Int. J. Neuropsychopharmacol., under review.","DOI":"10.1093\/ijnp\/pyab089"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.bbr.2016.09.029","article-title":"The olfactory bulbectomized rat as a model of depression: The hippocampal pathway","volume":"317","author":"Iannitti","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cipriani, A., Santilli, C., Furukawa, T.A., Signoretti, A., Nakagawa, A., McGuire, H., Churchill, R., and Barbui, C. (2009). Escitalopram versus other antidepressive agents for depression. Cochrane Database Syst. Rev., CD006532.","DOI":"10.1002\/14651858.CD006117.pub2"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.bbr.2012.09.035","article-title":"Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice","volume":"237","author":"Freitas","year":"2013","journal-title":"Behav. Brain. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.neuroscience.2017.05.021","article-title":"Chronic fluoxetine rescues changes in plasma membrane density of 5-HT1A autoreceptors and serotonin transporters in the olfactory bulbectomy rodent model of depression","volume":"356","author":"Riad","year":"2017","journal-title":"Neuroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1515\/hsz-2015-0267","article-title":"Signaling pathways regulating Homer1a expression: Implications for antidepressant therapy","volume":"397","author":"Serchov","year":"2016","journal-title":"Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dennis, S., Charney, E.J.N., Pamela, S., Joseph, D. (2017). Animals models of mood disorders. Neurobiology of Mental Illness, Oxford University Press. [5th ed.].","DOI":"10.1093\/med\/9780190681425.001.0001"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neuropharm.2018.11.006","article-title":"Synergistic effect of aripiprazole and escitalopram in increasing serotonin but not norepinephrine neurotransmission in the rat hippocampus","volume":"146","author":"Ebrahimzadeh","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s40263-021-00803-2","article-title":"Predictors of Quality of Life Improvement with Escitalopram and Adjunctive Aripiprazole in Patients with Major Depressive Disorder: A CAN-BIND Study Report","volume":"35","author":"Morton","year":"2021","journal-title":"CNS Drugs"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"796","DOI":"10.30773\/pi.2020.0017","article-title":"Efficacy of Buspirone Augmentation of Escitalopram in Patients with Major Depressive Disorder with and without Atypical Features: A Randomized, 8 Week, Multicenter, Open-Label Clinical Trial","volume":"17","author":"Shin","year":"2020","journal-title":"Psychiatry Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1016\/j.bmc.2017.03.057","article-title":"Novel 5-HT","volume":"25","author":"Canale","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s00213-007-1052-0","article-title":"Juvenile rats in the forced-swim test model the human response to antidepressant treatment for pediatric depression","volume":"197","author":"Reed","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_38","first-page":"37","article-title":"Study on the effect of EMD386088, a 5-HT","volume":"391","author":"Siwek","year":"2018","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhu, H., Tao, Y., Wang, T., Zhou, J., Yang, Y., Cheng, L., Zhang, W., Huang, F., and Wu, X. (2020). Long-term stability and characteristics of behavioral, biochemical, and molecular markers of three different rodent models for depression. Brain Behav., 10.","DOI":"10.1002\/brb3.1508"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41583-020-0292-4","article-title":"Circuits and functions of the lateral habenula in health and in disease","volume":"21","author":"Hu","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.conb.2017.10.024","article-title":"Lateral habenula in the pathophysiology of depression","volume":"48","author":"Yang","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00406-016-0675-8","article-title":"Habenula volume increases with disease severity in unmedicated major depressive disorder as revealed by 7T MRI","volume":"267","author":"Schmidt","year":"2017","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1016\/j.biopsych.2009.08.027","article-title":"Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient","volume":"67","author":"Sartorius","year":"2010","journal-title":"Biol. Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1016\/j.brs.2019.05.010","article-title":"Habenula deep brain stimulation for refractory bipolar disorder","volume":"12","author":"Zhang","year":"2019","journal-title":"Brain Stimul."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature25509","article-title":"Ketamine blocks bursting in the lateral habenula to rapidly relieve depression","volume":"554","author":"Yang","year":"2018","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.neuron.2013.08.023","article-title":"A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward","volume":"80","author":"Stamatakis","year":"2013","journal-title":"Neuron"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1007\/s00429-018-1623-3","article-title":"Dorsal raphe projection inhibits the excitatory inputs on lateral habenula and alleviates depressive behaviors in rats","volume":"223","author":"Zhang","year":"2018","journal-title":"Brain Struct. Funct."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Fuxe, K., and Borroto-Escuela, D. (2018). Small Interference RNA Knockdown Rats in Behavioral Functions: GALR1\/GALR2 Heteroreceptor in Anxiety and Depression-Like Behavior. Receptor-Receptor Interactions in the Central Nervous System, Springer.","DOI":"10.1007\/978-1-4939-8576-0"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10848\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:10:15Z","timestamp":1760166615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10848"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,7]]},"references-count":48,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910848"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910848","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,7]]}}}