Animal Models of Depression: Classification and Relevant Validation Criteria

  • Santiago Márquez-Herrero
  • José Ignacio Hernández
  • Osvaldo Soler
  • Manuel Alejandro Guevara
  • Pascual Ángel Gargiulo


In the last years, a change in the ways of understanding and applying experimental models has been observed. Taking into account the conceptual difference between a model, a test, and a paradigm, a classification of the current animal models of depression is proposed. This classification follows an empirical criterion and is catalogued according to the practical nature of the technical procedures implied in the experimental process. It diverges in some sense from the one proposed by Willner. He described 18 models following the conceptual rigor of his classical notions about validation criteria. It is worth considering that the design of a model fundamentally aims at imitating the etiological process of transformation from a healthy organism into a pathological organism through a vulnerability state in time. Most experimental models employ either genetic manipulations or some type of environmental stress or even a combination of both. Validating those experimental models is required in order to certify the applicability of their findings and abbreviate the distance between basic research and medical practice. Each one serves a particular purpose which determines the validation criteria that it must satisfy. Finally, the classification here proposed is open to modifications regarding future discoveries and findings in the field of neurobiological research and human phenomenology that may change our comprehension of the experimental models currently in use.


Depressive disorder Animal model Classification Translational research Rat 


  1. 1.
    Willner P. The validity of animal models of depression. Psychopharmacology (Berl). 1984;83(1):1–16.PubMedGoogle Scholar
  2. 2.
    Slattery DA, Cryan JF. Modelling depression in animals: at the interface of reward and stress pathways. Psychopharmacology (Berl). 2017;234(9-10):1451–65.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl). 2005;177(3):245–55.PubMedGoogle Scholar
  4. 4.
    Petit-Demouliere B, Chenu F, Bourin M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology. 2005;177(3):245–55.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Krishnan V, Nestler EJ. Animal models of depression: molecular perspectives. Curr Top Behav Neurosci. 2011;7:121–47.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Bhat SA, Wani AL, Ara A. Animal models of depression and their criteria of validation. J Chem Pharm Res. 2014;6(10):123–30.Google Scholar
  7. 7.
    Czéh B, Fuchs E, Wiborg O, Simon M. Animal models of major depression and their clinical implications. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;64:293–310.Google Scholar
  8. 8.
    Abelaira HM, Réus GZ, Quevedo J. Animal models as tools to study the pathophysiology of depression. Rev Bras Psiquiatr. 2013;35(Suppl 2):S112–20.PubMedGoogle Scholar
  9. 9.
    Wiborg O. Chronic mild stress for modeling anhedonia. Cell Tissue Res. 2013;354(1):155–69.PubMedGoogle Scholar
  10. 10.
    Belzung C, Lemoine M. Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression. Biol Mood Anxiety Disord. 2011;1(1):9.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Hill MN, Hellemans KG, Verma P, Gorzalka BB, Weinberg J. Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav Rev. 2012;36(9):2085–117.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Franceschelli A, Herchick S, Thelen C, Papadopoulou-Daifoti Z, Pitychoutis PM. Sex differences in the chronic mild stress model of depression. Behav Pharmacol. 2014;25(5–6):372–83.PubMedGoogle Scholar
  13. 13.
    Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13(10):1161–9.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Koolhaas JM, De Boer SF, De Rutter AJ, Meerlo P, Sgoifo A. Social stress in rats and mice. Acta Physiol Scand Suppl. 1997;640:69–72.PubMedGoogle Scholar
  15. 15.
    Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR J. 2014;55(2):221–32.PubMedGoogle Scholar
  16. 16.
    McEwen BS, Karatsoreos IN. Sleep deprivation and circadian disruption: stress, allostasis, and allostatic load. Sleep Med Clin. 2015;10(1):1–10.PubMedGoogle Scholar
  17. 17.
    Vollmayr B, Gass P. Learned helplessness: unique features and translational value of a cognitive depression model. Cell Tissue Res. 2013;354(1):171–8.PubMedGoogle Scholar
  18. 18.
    Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev. 2005;29(4–5):571–625.PubMedGoogle Scholar
  19. 19.
    Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev. 2005;29(4–5):547–69.Google Scholar
  20. 20.
    Barkus C. Genetic mouse models of depression. Curr Topics Behav Neurosci. 2013;14:55–78.Google Scholar
  21. 21.
    Wegener G, Mathe AA, Neumann ID. Selectively bred rodents as models of depression and anxiety. Curr Top Behav Neurosci. 2012;12:139–87.PubMedGoogle Scholar
  22. 22.
    Touriño C, Ada E-R, de Lecea L. Optogenetics in psychiatric diseases. Curr Opin Neurobiol. 2013;23(3):430–5.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Gellén B, Völgyi K, Györffy BA, Balogh B, Darula Z, Hunyadi-Gulyás É, Baracskay P, Czurkó A, Hernádi I, Juhász G, Dobolyi Á, Kékesi KA. Proteomic investigation of the prefrontal cortex in the rat clomipramine model of depression. J Proteome. 2016.Google Scholar
  24. 24.
    Vázquez-Palacios G, Bonilla-Jaime H, Velázquez-Moctezuma J. Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine. Prog Neuro-Psychopharmacol Biol Psychiatry. 2005;29(1):39–46.Google Scholar
  25. 25.
    Della Gioia N, Hannestad J. A critical review of human endotoxin administration as an experimental paradigm of depression. Neurosci Biobehav Rev. 2010;34(1):130–43.Google Scholar
  26. 26.
    Geyer MA, Markou A. Animal models of psychiatric disorders. In: Bloom FE, Kupfer D, editors. Psychopharmacology: fourth generation of progress. New York: Raven; 1995. p. 787–98.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Santiago Márquez-Herrero
    • 1
  • José Ignacio Hernández
    • 1
  • Osvaldo Soler
    • 1
  • Manuel Alejandro Guevara
    • 1
  • Pascual Ángel Gargiulo
    • 2
    • 3
  1. 1.Laboratory of Neurosciences and Experimental Psychology National Council of Scientific and Technical Research (CONICET), Area of Pharmacology, Department of Pathology, Faculty of Medical SciencesNational University of CuyoMendozaArgentina
  2. 2.Cathedra of Psychopathology, Faculty of Humanities and Educational SciencesCatholic University of ArgentinaMendozaArgentina
  3. 3.Laboratory of Neurosciences and Experimental Psychology, Area of Pharmacology, Department of Pathology, Faculty of Medical Sciences, National University of CuyoCouncil of Scientific and Technological Research (CONICET)MendozaArgentina

Personalised recommendations