Psychiatric Disorders pp 125-144

Part of the Methods in Molecular Biology book series (MIMB, volume 829)

Modeling Depression in Animal Models


Animal models and preclinical tests have played large roles in the development of antidepressant drugs and are likely to continue to play important roles. In the present communication, the main animal models of depression have been described and reviewed. These models include the Flinders sensitive line (FSL) rat, the Wistar Kyoto (WKY) rat, the fawn-hooded (FH) rat, and the learned helpless (LH) rat. In addition, the materials used to assess the behavior of these rats, including swim tanks, drinking tubes, and an open field apparatus, have been discussed. Finally, the methods used in collecting the relevant behaviors in the animal models are described. These include the procedures used in the forced swim test and chronic mild stress protocols, including the sucrose preference test. It is concluded that the behavioral tests used to infer depressed-like behavior in rats will continue to provide useful data if the appropriate animals and proper methods are used.

Key words

Rat models of depression (FSL, WKY, FH, LH) Forced swim test Chronic mild stress Sucrose preference test Social interaction test 


  1. 1.
    Overstreet, D.H., Russell, R.W., Helps, S.C., and Messenger, M. (1979) Selective breeding for sensitivity to the anticholinesterase, DFP. Psychopharmacology 65, 15–20.PubMedCrossRefGoogle Scholar
  2. 2.
    Janowsky, D.S., Nurnberger, J.I.Jr., and Overstreet, D.H. (1994) Is cholinergic sensitivity a genetic marker for the affective disorders? Am. J. Med. Genet. 54, 335–344.PubMedCrossRefGoogle Scholar
  3. 3.
    Overstreet, D.H. (1986) Selective breeding for increased cholinergic function: Development of a new animal model of depression. Biol. Psychiatry 21, 49–58.PubMedCrossRefGoogle Scholar
  4. 4.
    Overstreet, D.H. (1993) The Flinders Sensitive Line rats: A genetic animal model of depression. Neurosci. Biobehav. Rev. 17, 5168.PubMedCrossRefGoogle Scholar
  5. 5.
    Schiller, G.D., Daws, L.C., Overstreet, D.H., Orbach, J. (1991) Lack of anxiety in an animal model of depression with cholinergic supersensitivity. Brain Res. Bull. 26, 433–435.PubMedCrossRefGoogle Scholar
  6. 6.
    Overstreet, D.H., Keeney, A., and Hogg, S. (2004) Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression. Eur. J. Pharmacol. 492, 195–201.PubMedCrossRefGoogle Scholar
  7. 7.
    Overstreet, D.H., Hlavka, J., Feighner, J.P., Nicolau, G., and Freed, J.S. (2004) Antidepressant-like effects of a novel pentapeptide, nemifitide, in an animal model of depression. Psychopharmacology 125, 303–309.CrossRefGoogle Scholar
  8. 8.
    Benca, R.M., Overstreet, D.H., Gillilland, M.A., Russell, D., Bergmann, B.M., and Obermeyer, W.H. (1996) Increased basal REM sleep but no difference in dark-induced induction or light suppression of REM sleep in Flinders rats with cholinergic supersensitivity. Neuropsychopharmacology 15, 45–51.PubMedCrossRefGoogle Scholar
  9. 9.
    Shiromani, P.J., Overstreet, D.H., Levy, D., Goodrich, S.S., and Gillin, J.C. (1988) Increased REM sleep in rats selectively bred for cholinergic hyperactivity. Neuropsycho-pharmacology 1, 127–133.PubMedCrossRefGoogle Scholar
  10. 10.
    Overstreet, D.H., Friedman, E.F., Mathe’, A.A., and Yadid, G. (2005) The Flinders Sensitive Line rat: A selectively bred putative animal model of depression. Neurosci. Biobehav. Rev. 29, 739–759.PubMedCrossRefGoogle Scholar
  11. 11.
    Yadid, G., Overstreet, D.H., and Zangen A. (2001) Limbic dopaminergic adaptation to a stressful stimulus in a rat model of depression. Brain Res. 896, 43–47.PubMedCrossRefGoogle Scholar
  12. 12.
    Jimenez-Vasquez, P.A., Overstreet, D.H., Mathe’, A.A. (2000) Neuropeptide Y in male and female brains of Flinders Sensitive Line, a rat model of depression. Effect of electroconvulsive stimuli. J. Psychiatric Res. 34, 405–412.Google Scholar
  13. 13.
    Elfving, B., Ploughmann, P.H, Muller H.K., Mathe’, A.A., Rosenberg, R., Wegener, G. (2010) Inverse correlation of brain and blood BDNF levels in a genetic rat model of depression. Internat. J. Neuropsychopharmacol 13, 563–572.CrossRefGoogle Scholar
  14. 14.
    Zangen, A., Overstreet, D.H., and Yadid, G. (1997) High serotonin and 5-Hydroxindoleacetic acid levels in limbic regions in a rat model of depression: normalization by chronic antidepressant treatment. J. Neurochem. 69, 2477–2483.PubMedCrossRefGoogle Scholar
  15. 15.
    Zangen, A., Overstreet, D.H., and Yadid, G. (1999) Increased catecholamine levels in specific brain regions of a rat model of depression: normalization by chronic antidepressant treatment. Brain Res. 824, 243–250.PubMedCrossRefGoogle Scholar
  16. 16.
    Roth-Deri, I., Friedman A., Abraham L., Lax, E., Flaumenhaff Y., Dikshtein Y, Yadid, G. (2009) Antidepressant treatment facilitates dopamine release and drug seeking behavior in a genetic animal model of depression. Eur. J. Neurosci. 30, 485–492.PubMedCrossRefGoogle Scholar
  17. 17.
    Kotsovolou O., Ingelman-Sundberg M., Lang, M.A., Marselos, M., Overstreet, D.H., Papadopolou-Daifoti, A., Johanson, I., Fotopoulos, A., Konstandi, M. (2010) Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression. Prog. Neuropschopharmacol. Biol Psychiatry June 4 [Epub ahead of print].Google Scholar
  18. 18.
    Musazzi L., Mallei A, Tardito, D.,, Gruber, S.H., El Khoury A., Racagni, G., Mathe’, A.A., and Popoli, M. (2010) Early-life stress and antidepressant treatment involve synaptic signaling and ERK kinases in a gene-environment model of depression. J. Psychiatric Res. 44, 511–510.CrossRefGoogle Scholar
  19. 19.
    Koavacev’, T., Skelin, I., Diksic, M. (2010) Chronic fluoxetine treatment has a larger effect on the density of a serotonin transporter in Flinders Sensitive Line (FSL) rat model of depression than in normal rats. Synapse 64, 231–240.CrossRefGoogle Scholar
  20. 20.
    Jaehne, E.J., Majumder, I., Salem, A., Irvine, R.J. (2010) Increased effects of 3,4-methylenedioxymethamphetamaine (ecstasy) in a rat model of depression. Addict. Biol. Feb. 26, Epub ahead of print.Google Scholar
  21. 21.
    Wegner, G,, Harvey, B.H., Bonelfleld, G., Mjuller, H.K., Volke V., Overstreet, D.H., and Elfving, G. (2010) Increased stress-evoked nitric oxide signaling in the Flinders Sensitive Line (FSL) rat: a genetic animal model of depression. Int. J. Neuropsychopharmacol 13, 563–572.CrossRefGoogle Scholar
  22. 22.
    Liebenberg, N., Harvey, B.H., Brand, L., and Brink, C.B. (2010) Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependence in a genetic rat model of depression. Behav. Pharmacol. June [Epub ahead of print].Google Scholar
  23. 23.
    Pucilowski, O., and Overstreet, D.H. (1993) Effect of chronic antidepressant treatment on responses to apomorphine in selectively bred rat strains. Brain Res. Bull. 32, 471–475.PubMedCrossRefGoogle Scholar
  24. 24.
    Overstreet, D.H., Rettori, M.C., Delagrange, P., Gardiola-Lemaitre, B. (1998) Effects of melatonin receptor ligands on swim test immobility. NeuroReport 9, 249–253.PubMedCrossRefGoogle Scholar
  25. 25.
    Tizabi, Y., Overstreet, D.H., Rezvani, A.H., Louis, V.A., Clark, E.Jr., Janowsky, D.S., Kling, M.A. (1999) Antidepressant effect of nicotine in an animal model of depression. Psychopharmacology 142, 193–199.PubMedCrossRefGoogle Scholar
  26. 26.
    Overstreet, D.H. and Griebel, G. (2004) Antidepressant-like effect of the CRF1 receptor antagonist SSR125543 in an animal model of depression. Eur. J. Pharmacol. 497, 49–53.PubMedCrossRefGoogle Scholar
  27. 27.
    Overstreet, D.H. and Griebel, G. (2005) Antidepressant-like effects of the vasopressin V1b antagonist SSR149 415 in the Flinders Sensitive Line rat. Pharmacol. Biochem. Behav. 82, 223–227.PubMedCrossRefGoogle Scholar
  28. 28.
    Overstreet, D.H., Stemmelin J., and Griebel, G. (2008) Confirmation of the antidepressant potential of the selective beta3 adrenoceptor agonist amibegron in an animal model of depression. Pharmacol. Biochem. Behav. 89, 623–626.PubMedCrossRefGoogle Scholar
  29. 29.
    Walker, M.W., Wolinsky, T.D., Jabion, V., Chandransnan, G., Zhonf, H., Huang, X., Miller, S., Hegde, L.G., Marsteller, D.A., Marzabuti, Papp, M., Overstreet, D.H., Gerald, L.F., and Craig, D.A. (2010) The novel neuropeptide Y Y5 receptor antagonist, LuAA33810 [N-[[trans-4-[(4,5-dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide] exerts anxiolytic and antidepressant effects in rat models of stress sensitivity. J. Pharmacol. Exp. Ther. 328, 900–911.Google Scholar
  30. 30.
    Overstreet, D.H., Fredericks, K., Knapp, D., Breese, G., McMichael, J. (2010) Nerve growth factor (NGF) has novel antidepressant-like properties in rats. Pharmacol. Biochem. Behav. 94, 553–560.PubMedCrossRefGoogle Scholar
  31. 31.
    Overstreet, D.H., Naimoli, V.M., and Griebel, G. (2010) Saredutant, an NK2 receptor antagonist, has both antidepressant-like effects and synergizes with desipramine in an animal model of depression. Pharmacol. Biochem. Behav. 96, 206–210.PubMedCrossRefGoogle Scholar
  32. 32.
    Overstreet, D.H., Miller, C.S., Janowsky, D.S., and Russell, R.W. (1996) Potential animal model of multiple chemical sensitivity with cholinergic supersensitivity. Toxicology 111, 119–134.PubMedCrossRefGoogle Scholar
  33. 33.
    Mattson, H., Arani, Z., Astin, M., Bagati, A., Overstreet, D.H., and Lehmann, A. (2005) Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat. Neurogastrenterol. Motil. 17, 166–174.CrossRefGoogle Scholar
  34. 34.
    Padley, J.R., Overstreet, D.H., Pilowsky, P., Goodchild, A.K. (2005) Impaired cardiac and sympathetic autonomic control in rats differing in acetylcholine receptor sensitivity. Am. J. Physiol. Circ. Physiol. 289, H1985–H1992.CrossRefGoogle Scholar
  35. 35.
    Friedman, E.M., Becker, K.A., Overstreet, D.H., Laurence, D.A. (2002) Reduced primary antibody responses in a genetic animal of depression. Psychosom. Med. 64, 267–273.PubMedGoogle Scholar
  36. 36.
    Lerman, L.O., Chader, A.R., Sica, V., Napoli, C. (2005) Animal models of hypertension: an overview. J. Lab. Clin. Med. 146, 160–173.PubMedCrossRefGoogle Scholar
  37. 37.
    Pare’, W.P. (1989) “Behavioral despair” test predicts stress ulcer in WKY rats. Physiol. Behav. 46, 483–487.CrossRefGoogle Scholar
  38. 38.
    Pare’, W.P. (1989) Stress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats. Physiol Behav 46, 993–996.CrossRefGoogle Scholar
  39. 39.
    Pare, W.P. (1992) The performance of the WKY rat on three tests of emotional behavior. Physiol. Behav. 51, 1051–1056.PubMedCrossRefGoogle Scholar
  40. 40.
    Will, C.C, Aird, F., and Redei, E.E. (2003) Selectively bred Wistat-Kyoto rats: an animal model of depression and hyper-responsiveness to antidepressants. Molec. Psychiatry 8, 925–932.CrossRefGoogle Scholar
  41. 41.
    Solberg C., Baum, A.E., Ahmadiyeh, N., Shimomura K., Li, R., Tarek, F.W., Churchill, C.A., Takahashi, J.S., and Redei EE. (2004) Sex- and lineage-specific inheritance of depression-like behavior in the rat. Mamm. Genome 15, 648–662.PubMedCrossRefGoogle Scholar
  42. 42.
    Carr, D.R., Bangasser, D.A, Bethea, T., Young, M, Valentino, R.J., Lucki, I. (2010) Antidepressant-like effects of kappa opioid receptor antagonist in Wistar Kyoto rats. Neuropsychopharmacology 35, 752–763.PubMedCrossRefGoogle Scholar
  43. 43.
    Jeannotte, A.M., McCarthy, J.G., Redei E.E., Sidhu, A. (2009) Desipramine modulation of alpha-gamma-synuclein and the norepinephrine transporter in an animal model of depression. 34, 987–998.Google Scholar
  44. 44.
    Malkesman, O., Braw, Y., and Weller, A. (2007) Assessment of antidepressant and anxiolytic properties of NK1 antagonists and substance P in Wistar Kyoto rats. Physiol. Behav. 90, 619–625.PubMedCrossRefGoogle Scholar
  45. 45.
    Malkesman, O., and Weller, A. (2009) Two different putative genetic animal models of childhood depression – a review. Prog. Neurobiol. 88, 153–169.PubMedCrossRefGoogle Scholar
  46. 46.
    Rezvani, A.H., Overstreet, D.H., and Janowsky, D.S. (1990) Genetic serotonin deficiency and alcohol preference in the Fawn-Hooded rat. Alcohol Alcohol. 25, 573–575.PubMedGoogle Scholar
  47. 47.
    Rezvani, A.H., Parsian, A., and Overstreet, D.H. (2002) Fawn-Hooded (FH/Wjd) rat: a genetic animal model of cormorbid depression and alcoholism. Psychiatric Genet. 12, 1–16.CrossRefGoogle Scholar
  48. 48.
    Overstreet, D.H., Rezvani, A.H., Djouma E., Parsian, P., and Lawrence, A.J. (2007) Depression-like behavior and high alcohol drinking co-occur in the Fawn-Hooded (FH/Wjd) rat but appear to be under independent genetic control. Neurosci. Biobehav. Rev. 31, 103–114.PubMedCrossRefGoogle Scholar
  49. 49.
    Rezvani, A.H., Overstreet, D.H., Cleves, M., Parsian, A. (2007) Further genetic characterization of the Fawn-Hooded (FH/Wjd) rat, a genetic animal model of comorbid depression and alcoholism. Psychiatric Genet. 17, 77–83.CrossRefGoogle Scholar
  50. 50.
    Patra, B., Overstreet, D.H., Rezvani, A.H., Cleves, M., Parsian, A. (2007) Analysis of alcohol related phenotypes in F2 progeny derived from FH/Wjd and ACI/N strains reveals independent measures and sex differences. Behav. Brain Res. 177, 37–44.PubMedCrossRefGoogle Scholar
  51. 51.
    Overstreet, D.H., Rezvani, A.H., Cowen, M., Chen, F., and Lawrence, A.J. (2006) Modulation of high alcohol drinking in the inbred Fawn-Hooded (FH/Wjd) rat strain: Implications for treatment. Addict. Biol. 11, 356–373.PubMedCrossRefGoogle Scholar
  52. 52.
    Overstreet, D.H., Rezvani, A.H., Parsian, A. (2005) Chronic fluoxetine treatment reduces swim test immobility but not alcohol intake in the Fawn-Hooded rat, an animal model of depression/alcoholism. Presented at35th annual meeting of the Society for Neuroscience, 2005.Google Scholar
  53. 53.
    Pettinati, H.M. (2004) Antidepressant treatment of co-occurring depression and alcohol dependence. Biol. Psychiatry 56, 785–792.PubMedCrossRefGoogle Scholar
  54. 54.
    Henn, F.A., and Vollmayr, G. (2005). Stress models of depression: Forming genetically vulnerable strains. Neurosci. Biobehav. Rev. 29, 799–804.PubMedCrossRefGoogle Scholar
  55. 55.
    Seligmann, M.E., ands Beagley, C. (1975) Learned helplessness in the rat. J. Comp. Physiol. Psychol. 88, 534–541.Google Scholar
  56. 56.
    Jesberger, J.A. and Richardson, J.S. (1985) Animal models of depression: Parallels and correlates to severe depression in humans. Biol. Psychiatry 20, 764–784.PubMedCrossRefGoogle Scholar
  57. 57.
    Vollmayr, G. and Henn, FA (2001) Learned helplessness in the rat: improvements in validity and reliability. Brain Res. Brain Res. Protoc. 8, 1–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Sanchi-Segura. C., Spanagel R., Henn, F.A., Vollmayr, G. (2005) Reduced sensitivity to sucrose in rats bred for helplessness: a study using the matching law. Behav. Pharmacol. 16, 267–270.CrossRefGoogle Scholar
  59. 59.
    Bhattamisra, S.K., Khanna, S.K., Agrawal, A.K., Singh, P.U., Singh, S.K. (2008). Antidepressant activity of standardardized extract of Marsilea minuta Linn. J. Ethnopharmacol. 117, 51–57.PubMedCrossRefGoogle Scholar
  60. 60.
    Bertaina-Anglade, V., Larochelle, C.D., and Scheller, A.H. (2006) Antidepressant properties of rotigotine in experimental models of depression. Eur. J. Pharmacol. 548, 106–114.PubMedCrossRefGoogle Scholar
  61. 61.
    Weiss, J.M., Cierpial, M.R., West, C.H. (1998) Selective breeding of rats for high and low motor activity in a swim test. Pharmacol. Bochem. Behav. 61, 49–66.CrossRefGoogle Scholar
  62. 62.
    West, C.H., and Weiss, J.M. (1998) Effects of antidepressant drugs on rats bred for low activity in the swim test. Pharmacol. Biochem. Behav, 61, 67–79.Google Scholar
  63. 63.
    West, C.H. and Weiss, J.M. (2005) A selective test for antidepressant treatments using rats bred for stress-induced reduction of motor activity in the swim test. Psychopharmacoloogy 182, 9–23.CrossRefGoogle Scholar
  64. 64.
    Piras, G., Giorgi, O., and Corda, M.G. (2010) Effects of antidepressants on the performance in the forced swim test of two psychogenetically selected lines of rats that differ in coping strategies to aversive conditions. Psychopharmacology June 30 [Epub ahead of print].Google Scholar
  65. 65.
    Liebsch, G., Montkowski, A., Holsboer, F., Landgraph, R. (1998) Behavioral profile of two Wistar rat lines selectively bred for high or low anxiety-related behavior. Behav. Brain Res. 94, 301–310.PubMedCrossRefGoogle Scholar
  66. 66.
    Landgraph, R., Wigger, A. (2003) Born to be anxious, Neuroendocrine and genetic correlates of trait anxiety in HAB rats. Stress 6, 111–119.CrossRefGoogle Scholar
  67. 67.
    Overstreet, D.H., Rezvani, A.H., Pucilowski, O., Gause, L., and Janowsky, D.S. (1984) Rapid selection for serotonin-1A sensitivity in rats. Psychiat. Genet. 4, 57–62.CrossRefGoogle Scholar
  68. 68.
    Overstreet, D.H., Rezvani, A.H., Knapp, D.J., Crews, F.T., and Janowsky, D.S. (1996) Further selection of rat lines differing in 5-HT-1A receptor sensitivity. Behavioral and functional correlates. Psychiat. Genet. 6, 107–117.Google Scholar
  69. 69.
    Overstreet, D.H., Daws, L.C., Schiller, G.R., Orbach, J., and Janowsky, D.S. (1998) Cholinergic/serotonergic interactions in hypothermia: implications for models of depression. Pharmacol. Biochem. Behav. 59, 777–785.PubMedCrossRefGoogle Scholar
  70. 70.
    Overstreet, D.H. (2007) The open field test for two. J. Psychopharmacol. 21, 140.PubMedCrossRefGoogle Scholar
  71. 71.
    Reed, A.L., Anderson, J.D., Bylund, D.B., Petty, F, ElRefaey, H., and Happe, H.K, (2009) Treatment with escitalopram but not imipramine decreases escape latency times in a learned helplessness model using juvenile rats. Neuropsychopharmacology 134, 319–329.Google Scholar
  72. 72.
    Valentine, G., Dow, A., Banasr, M., Pittman, B., Duman, R. (2008) Differential effects of chronic antidepressant treatment on shuttle box escape deficits induced by uncontrollable stress. Psychopharmacology 200, 585–596.PubMedCrossRefGoogle Scholar
  73. 73.
    Willner, P. (1977) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134, 319–319.CrossRefGoogle Scholar
  74. 74.
    Willner, P. (2005) Chronic mild stress (CMS) revisited. Consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52, 90–110.Google Scholar
  75. 75.
    Cryan, J.F., Valentino, R.J., and Lucki, I. (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swim test. Neurosci. Biobehav. Rev. 29, 547–568.PubMedCrossRefGoogle Scholar
  76. 76.
    Overstreet, D.H., Kampov-Polevoy, A.B., Rezvani, A.H., Murrelle, L., Halikas, J.A., Janowsky, D.S. (1993) Saccharin intake predicts ethanol intake in genetically heterogeneous rats as well as different rat strains. Alcohol. Clin. Exp. Res. 17, 366–369.PubMedCrossRefGoogle Scholar
  77. 77.
    Pucilowski, O., Overstreet, D.H., Rezvani, A.H., Janowsky, D.S. (1993) Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression. Physiol. Behav. 54, 1215–1220.PubMedCrossRefGoogle Scholar
  78. 78.
    File, S.E., and Seth, P. (2003) A review of 25 years of the social interaction test. Eur. J. Pharmacol. 463, 35–53.PubMedCrossRefGoogle Scholar
  79. 79.
    Overstreet, D.H., Knapp, D.J., Breese, G.R. (2002) Accentuated decreases in social interaction in rat subjected to repeated ethanol withdrawals. Alcohol. Clin. Exp. Res. 22, 159–164.Google Scholar
  80. 80.
    Overstreet, D.H., Knapp, D.J., Breese, G.R. (2004) Modulation of multiple ethanol withdrawal-induced anxiety-like behavior by CRF and CRF1 receptors. Pharmacol. Biochem. Behav. 77, 405–413.PubMedCrossRefGoogle Scholar
  81. 81.
    Overstreet, D.H., Knapp, D.L., Moy, S.S., Breese, G.R. (2003) A 5-HT1A agonist and a 5-HT2C antagonist reduce social interaction deficit induced by multiple ethanol withdrawals in rat. Psychopharmacology 167, 344–352.PubMedGoogle Scholar
  82. 82.
    Overstreet, D.H., Rezvani, A.H., and Janowsky, D.S. (1990) Impaired active avoidance responding in rats selectively bred for increased cholinergic function. Physiol. Behav. 47, 787–788.PubMedCrossRefGoogle Scholar
  83. 83.
    Dettke, M.S., Rickels, M., Lucki, I. (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psycho­pharmacology 121, 66–72.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Psychiatry and Center for Alcohol StudiesUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations