{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:45:08Z","timestamp":1760233508277,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The forced swim stress test (FST) is widely used for screening pharmacological or non-pharmacological strategies with potential antidepressant activities. Recent data have suggested that repeated FST for five consecutive days (i.e., 5d-RFSS) could be used to generate a robust depressive-like phenotype in mice. However, the face, construct, and predictive validities of 5d-RFSS have been recently challenged. This study took advantage of recent findings showing that mice vulnerability to anxiety is enhanced when animals are stressed during the dark phase, to provide new insight into the relevance of this model. Our results showed a progressive increase in time of immobility in 5d-RFSS mice relative to control non-stressed animals (sham). Three weeks later, we noticed that 5d-RFSS mice injected with the vehicle compound (Veh) still exhibited a high level of immobility in the FST whereas this behavior was reversed by the antidepressant drug amitriptyline (AMI). However, 5d-RFSS\/Veh and 5d-RFSS mice\/AMI mice showed normal performances in the open field, the novelty suppressed feeding and the tail suspension tests. Despite this lack of generalized behavioral deficits, an impairment of different parameters characterizing the hypothalamic-pituitary-adrenal (HPA) axis reactivity was evidenced in 5d-RFSS mice\/Veh but not in 5d-RFSS mice\/AMI. Despite anomalies in the HPA axis, the activity of the central serotonergic system remained unaffected in 5d-RFSS mice relative to controls. From our results, it is suggested that learned immobility does not replicate the broad spectrum of depressive symptoms observed in other chronic models of depression such as the unpredictable chronic mild stress (UCMS) model, the chronic social defeat stress (CSDS) model or chronic corticosterone (CORT) exposure but its influence on the HPA axis is remarkable. Further experiments are warranted to makes this model suitable for modelling depression and therefore refine its translational applicability.<\/jats:p>","DOI":"10.3390\/ijms22020937","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T04:55:31Z","timestamp":1611032131000},"page":"937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Learned Immobility Produces Enduring Impairment of the HPA Axis Reactivity in Mice without Replicating the Broad Spectrum of Depressive-Like Phenotype"],"prefix":"10.3390","volume":"22","author":[{"given":"S\u00e9bastien","family":"Bullich","sequence":"first","affiliation":[{"name":"Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Int\u00e9grative (CBI), Universit\u00e9 de Toulouse, CNRS UMR5169, UPS, 31062 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Delcourte","sequence":"additional","affiliation":[{"name":"INSERM, Stem Cell and Brain Research Institute U1208, University of Lyon, Universit\u00e9 Claude Bernard Lyon 1, 69500 Bron, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nasser","family":"Haddjeri","sequence":"additional","affiliation":[{"name":"INSERM, Stem Cell and Brain Research Institute U1208, University of Lyon, Universit\u00e9 Claude Bernard Lyon 1, 69500 Bron, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6873-9966","authenticated-orcid":false,"given":"Bruno P.","family":"Guiard","sequence":"additional","affiliation":[{"name":"Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Int\u00e9grative (CBI), Universit\u00e9 de Toulouse, CNRS UMR5169, UPS, 31062 Toulouse, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/nature07455","article-title":"The molecular neurobiology of depression","volume":"455","author":"Krishnan","year":"2008","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.biopsych.2020.01.012","article-title":"Causes and Consequences of Diagnostic Heterogeneity in Depression: Paths to Discovering Novel Biological Depression Subtypes","volume":"88","author":"Lynch","year":"2020","journal-title":"Biol. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.pnpbp.2017.04.008","article-title":"The recent progress in animal models of depression","volume":"77","author":"Wang","year":"2017","journal-title":"Prog. Neuropsy-chopharmacol. Biol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1073\/pnas.97.1.325","article-title":"Pronounced and sustained central hypernor-adrenergic function in major depression with melancholic features: Relation to hypercortisolism and corticotropin-releasing hormone","volume":"97","author":"Wong","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.neuron.2009.04.017","article-title":"Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety\/Depression","volume":"62","author":"David","year":"2009","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/s41380-019-0548-4","article-title":"Antidepressant efficacy of a se-lective organic cation transporter blocker in a mouse model of depression","volume":"25","author":"Coutens","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3389\/fnbeh.2014.00136","article-title":"Learning and memory impairments in a neuro-endocrine mouse model of anxiety\/depression","volume":"8","author":"Darcet","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.neuroscience.2014.05.050","article-title":"NREM sleep hypersomnia and reduced sleep\/wake continuity in a neuroendocrine mouse model of anxiety\/depression based on chronic corticosterone administration","volume":"274","author":"Hache","year":"2014","journal-title":"Neuroscience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1097\/WNR.0b013e328353d70a","article-title":"Antinociceptive effects of fluoxetine in a mouse model of anxiety\/depression","volume":"23","author":"Hache","year":"2012","journal-title":"NeuroReport"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e253","DOI":"10.1038\/tp.2013.30","article-title":"BDNF overexpression in mouse hippocampal astrocytes promotes local neuro-genesis and elicits anxiolytic-like activities","volume":"3","author":"Quesseveur","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1124\/mol.111.075796","article-title":"Functional Status of Somatodendritic Serotonin 1A Autoreceptor after Long-Term Treatment with Fluoxetine in a Mouse Model of Anxiety\/Depression Based on Repeated Corticosterone Administration","volume":"81","author":"Rainer","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"462","DOI":"10.3389\/fphar.2017.00462","article-title":"S 47445 Produces Antide-pressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms","volume":"8","author":"Guilloux","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1037\/pha0000112","article-title":"Chronic corticosterone administration effects on behavioral emotionality in female c57bl6 mice","volume":"25","author":"Mekiri","year":"2017","journal-title":"Exp. Clin. Psychopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1503\/jpn.150205","article-title":"Why is depression more prevalent in women?","volume":"40","author":"Albert","year":"2015","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S0006-3223(02)01405-1","article-title":"Preclinical models: Status of basic research in depression","volume":"52","author":"Nestler","year":"2002","journal-title":"Biol. Psychiatry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"234","DOI":"10.2174\/1570159X15666170818095105","article-title":"Neurobiological Mechanisms of Stress Resilience and Implications for the Aged Population","volume":"16","author":"Faye","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.psyneuen.2015.08.028","article-title":"Immobility in the forced swim test is adaptive and does not reflect depression","volume":"62","author":"Molendijk","year":"2015","journal-title":"Psychoneuroendocrinology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mul, J.D., Zheng, J., and Goodyear, L.J. (2016). Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL\/6J and BALB\/cJ Mice. Eneuro, 3.","DOI":"10.1523\/ENEURO.0201-16.2016"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16464","DOI":"10.1523\/JNEUROSCI.1542-11.2011","article-title":"Increase in Cortical Pyramidal Cell Excitability Accompanies Depression-Like Behavior in Mice: A Transcranial Magnetic Stimulation Study","volume":"31","author":"Sun","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Delcourte, S., Dkhissi-Benyahya, O., Cooper, H., and Haddjeri, N. (2017). Stress Models of Depression: A Question of Bad Timing. Eneuro, 4.","DOI":"10.1523\/ENEURO.0045-17.2017"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0014-2999(03)01326-8","article-title":"Stress-induced hyperthermia and anxiety: Pharmacological validation","volume":"463","author":"Olivier","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/j.neubiorev.2008.04.006","article-title":"Corticosteroid-serotonin interactions in the neurobiological mecha-nisms of stress-related disorders","volume":"32","author":"Lanfumey","year":"2008","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1017\/S1461145711000484","article-title":"Altered response to the selective serotonin reuptake inhibitor escitalopram in mice heterozygous for the serotonin transporter: An electrophysiological and neurochemical study","volume":"15","author":"Guiard","year":"2011","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Karatsoreos, I.N. (2014). Links between Circadian Rhythms and Psychiatric Disease. Front. Behav. Neurosci., 8.","DOI":"10.3389\/fnbeh.2014.00162"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3109\/07853890.2013.866440","article-title":"Circadian abnormalities in a mouse model of high trait anxiety and depression","volume":"46","author":"Griesauer","year":"2014","journal-title":"Ann. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Anyan, J., Verwey, M., and Amir, S. (2017). Individual differences in circadian locomotor parameters correlate with anxiety- and depres-sion-like behavior. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181375"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.neuron.2015.07.010","article-title":"Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depres-sive-like Behavior via Induction of Homer1a","volume":"87","author":"Serchov","year":"2015","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/j.1472-8206.1996.tb00610.x","article-title":"The effect of the potassium channel activator, cromakalim, on antidepressant drugs in the forced swimming test in mice","volume":"10","author":"Redrobe","year":"1996","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s00213-003-1518-7","article-title":"Sex differences in response to oral amitriptyline in three animal models of depression in C57BL\/6J mice","volume":"170","author":"Caldarone","year":"2003","journal-title":"Psychopharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejphar.2014.07.044","article-title":"Treatment of cognitive dysfunction in major depressive disorder\u2014a review of the preclinical evidence for efficacy of selective serotonin reuptake inhibitors, serotonin\u2013norepinephrine reuptake inhibitors and the multimodal-acting antidepressant vortioxetine","volume":"753","author":"Pehrson","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","first-page":"528","article-title":"The effect of amitriptyline on inhibitory avoidance in mice is dose-dependent","volume":"21","author":"Parra","year":"2009","journal-title":"Psicothema"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/0197-0186(89)90034-X","article-title":"Interaction of amitriptyline with muscarinic receptor subtypes in the rat brain","volume":"14","author":"Goldman","year":"1989","journal-title":"Neurochem. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1007\/BF00427455","article-title":"Effects of two antidepressants on memory performance in depressed outpatients: A double-blind study","volume":"84","author":"Lamping","year":"1984","journal-title":"Psychopharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Privitera, G.J., Misenheimer, M.L., and Doraiswamy, P.M. (2013). From weight loss to weight gain: Appetite changes in major depressive disorder as a mirror into brain-environment interactions. Front. Psychol., 4.","DOI":"10.3389\/fpsyg.2013.00873"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/npp.2008.76","article-title":"Corticolimbic Transcriptome Changes are State-Dependent and Region-Specific in a Rodent Model of Depression and of Antidepressant Reversal","volume":"34","author":"Surget","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Iio, W., Takagi, H., Ogawa, Y., Tsukahara, T., Chohnan, S., and Toyoda, A. (2014). Effects of chronic social defeat stress on peripheral leptin and its hypothalamic actions. BMC Neurosci., 15.","DOI":"10.1186\/1471-2202-15-72"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.npep.2004.06.004","article-title":"Stereological analysis of the hypothalamic hypocretin\/orexin neurons in an animal model of depression","volume":"38","author":"Allard","year":"2004","journal-title":"Neuropeptides"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1038\/npp.2012.70","article-title":"Neurogenesis-Independent Antidepressant-Like Effects on Behavior and Stress Axis Response of a Dual Orexin Receptor Antagonist in a Rodent Model of Depression","volume":"37","author":"Nollet","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1080\/23328940.2015.1070944","article-title":"Neural circuit for psychological stress-induced hyperthermia","volume":"2","author":"Nakamura","year":"2015","journal-title":"Temperature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.pnpbp.2004.05.007","article-title":"Stress-induced hyperthermia in the mouse: C-fos expression, corticosterone and temperature changes","volume":"28","author":"Veening","year":"2004","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0006-3223(00)01022-2","article-title":"Stress-induced hyperthermia in the 5-HT1A receptor knockout mouse is normal","volume":"49","author":"Pattij","year":"2001","journal-title":"Biol. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.pbb.2016.12.007","article-title":"Anxiogenic-like effects of fluoxetine render adult male rats vulnerable to the effects of a novel stress","volume":"153","author":"Gomez","year":"2017","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"105097","DOI":"10.1016\/j.psyneuen.2020.105097","article-title":"Adult neurogenesis augmentation attenuates anhedonia and HPA axis dysregulation in a mouse model of chronic stress and depression","volume":"124","author":"Eliwa","year":"2020","journal-title":"Psychoneuroendocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.neuroscience.2020.09.040","article-title":"A Citrus Based Sensory Functional Food Ingredient Induces Antidepressant-like Effects: Possible Involvement of an Interplay between the Olfactory and the Ser-otonergic Systems","volume":"451","author":"Coutens","year":"2020","journal-title":"Neuroscience"},{"key":"ref_45","first-page":"223","article-title":"Effects of antidepressant treatments on 5-HT neurotransmission: Electrophysiological and clinical studies","volume":"39","author":"Blier","year":"1984","journal-title":"Adv. Biochem. Psychopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.neuron.2009.12.003","article-title":"5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants","volume":"65","author":"Craige","year":"2010","journal-title":"Neuron"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/S0893-133X(99)00095-0","article-title":"Penetration of Amitriptyline, but Not of Fluoxetine, into Brain is Enhanced in Mice with Blood-Brain Barrier Deficiency Due to Mdr1a P-Glycoprotein Gene Disruption","volume":"22","author":"Uhr","year":"2000","journal-title":"Neuropsychopharmacology"},{"key":"ref_48","first-page":"730","article-title":"Depression: A new animal model sensitive to antidepressant treatments","volume":"266","author":"Porsolt","year":"1977","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5935","DOI":"10.1523\/JNEUROSCI.2904-18.2019","article-title":"Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids","volume":"39","author":"Zemdegs","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_50","unstructured":"Paxinos, G., and Franklin, K. (2019). The Mouse Brain in Stereotaxic Coordinates, Elsevier. [5th ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/937\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:12:41Z","timestamp":1760159561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,19]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22020937"],"URL":"https:\/\/doi.org\/10.3390\/ijms22020937","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,1,19]]}}}