Models of Affective Illness: Chronic Mild Stress in the Rat

Mariusz Papp1

1 Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.9
DOI:  10.1002/0471141755.ph0509s57
Online Posting Date:  June, 2012
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Described in this unit is a chronic mild stress (CMS) procedure used for predicting an antidepressant response. Following exposure to a variety of mild stressors for a period of several weeks, rat behavior is modified in a number of ways. Among these is a substantial reduction in consumption of a 1% sucrose solution. Chronic administration of antidepressant drugs reverses diminished enthusiasm for sucrose in these subjects. While most antidepressants must be administered for at least 3 to 5 weeks to normalize behavior, there are treatments that display a more rapid onset of action. More recently, it has been shown that the CMS‐induced deficit in sucrose consumption can also be reversed by second‐generation antipsychotics. Based on these findings, the CMS model can be employed in discovery programs aimed at identifying antianhedonic drugs (e.g., antidepressants and antipsychotics) that act more quickly than existing agents. Curr. Protoc. Pharmacol. 57:5.9.1‐5.9.11. © 2012 by John Wiley & Sons, Inc.

Keywords: chronic stress; animal model; depression; anhedonia; antidepressants

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Table of Contents

  • Introduction
  • Basic Protocol 1: Chronic Mild Stress as an Animal Model of Depression
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Basic Protocol 1: Chronic Mild Stress as an Animal Model of Depression

  • ∼120 g male hooded rats, aged ∼6 weeks (e.g., Wistar or Lister)
  • 1% (w/v) sucrose solution, final temperature ∼22°C (prepare fresh on the morning of use)
  • Test compounds
  • Opaque plastic cages, 40 × 25 × 15 cm
  • Sound‐proof rooms with stable environmental conditions (e.g., light/dark cycle, temperature, and humidity)
  • 250‐ml polythene drinking bottles with a stainless steel spout containing a ball‐bearing to minimize spillage (e.g., North Kent Plastic Cages Ltd.)
NOTE: Due to differences in reactivity to stressful stimuli, other rat strains (e.g., Long‐Evans or Sprague‐Dawley) are not recommended.NOTE: The exact concentration of the sucrose solution can vary from 1% to 2% according to the individual preferences of animals. The typical sucrose concentration is 1% and, at this concentration, normal, nonstressed animals drink 10 to 17 g of solution. If an animal drinks less than this, the concentration should be gradually increased in 0.1% increments to reach this range, but the sucrose solution should not exceed 2%.
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Literature Cited

   Adham, N., Gyertyán, I., Kiss, B., Gupta, S., Gruca, P., Litwa, E., and Papp, M. 2007. Antidepressant activity of RGH‐188, a potential antipsychotic with D3/D2 antagonist/partial agonist properties in a chronic mild stress‐induced anhedonia model. Neuroscience Meeting, Poster no. 906.11.
   Adham, N., Caron, MG., Gyertyán, I., Gruca, P., Kiss, B., Lason‐Tyburkiewicz, M., Szombathelyi, Z., and Papp, M. 2010. Cariprazine, a D3‐preferring dopamine D3/D2 receptor partial agonist, has antidepressant‐like activity with fast onset of action in the chronic mild stress‐induced anhedonia model. Neuropsychopharmacology 35:171.
   Brocco, M., Dekeyne, A., Papp, M., and Millan, M.J. 2006. Antidepressant‐like properties of the anti‐Parkinson agent, piribedil, in rodents: Mediation by dopamine D2 receptors. Behav. Pharmacol. 17:559‐572.
   Casarotto, P.C. and Andreatini, R. 2007. Repeated paroxetine treatment reverses anhedonia induced in rats by chronic mild stress or dexamethasone. Eur. Neuropsychopharmacol. 17:735‐742.
   Der‐Avakian, A. and Markou, A. 2012. The neurobiology of anhedonia and other reward‐related deficits. Trends Neurosci. 35:68‐77.
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   Marston, H.M., Martin, F.D., Papp, M., Gold, L., Wong, E.H., and Shahid, M. 2010. Attenuation of chronic mild stress‐induced “anhedonia” by asenapine is not associated with a “hedonic” profile in intracranial self‐stimulation. J. Psychopharmacol. 25:1388‐1398.
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   Moreau, J‐L., Jenck, F., Martin, J.R., Mortas, P., and Haefely, W.E. 1992. Antidepressant treatment prevents chronic mild stress‐induced anhedonia as assessed by ventral tegmentum self‐stimulation behaviour in rats. Eur. Neuropsychopharmacol. 2:43‐49.
   Moreau, J‐L., Scherschlict, R., Jenck, F., and Martin, J.R. 1995. Chronic mild stress‐induced anhedonia model of depression: Sleep abnormalities and curative effects of electroshock treatment. Behav. Pharmacol. 6:682‐687.
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   Muscat, R., Papp, M., and Willner, P. 1992. Reversal of stress‐induced anhedonia by the atypical antidepressants, fluoxetine and maprotoline. Psychopharmacology 109:433‐438.
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   Orsetti, M., Colella, L., Dellarole, A., Canonico, P.L., and Ghi, P. 2007b. Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats. Int. J. Neuropsychopharmacol. 10:345‐357.
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   Papp, M. and Wieronska, J. 2000. Antidepressant‐like effects of amisulpride in two animal models of depression. J. Psychopharmacol. 14:46‐52.
   Papp, M., Willner, P., and Muscat, R. 1991. An animal model of anhedonia: Attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology 104:255‐259.
   Papp, M., Lappas, S., Muscat, R., and Willner, P. 1992. Attenuation of place preference conditioning but not place aversion conditioning by chronic mild stress. J. Psychopharmacol. 6:352‐356.
   Papp, M., Muscat, R., and Willner, P. 1993. Subsensitivity to rewarding and locomotor stimulant effects of a dopamine agonist following chronic mild stress. Psychopharmacology 110:152‐158.
   Papp, M., Klimek, V., and Willner, P. 1994a. Effects of imipramine on serotonergic and beta‐adrenergic receptor binding in a realistic animal model of depression. Psychopharmacology 114:309‐314.
   Papp, M., Nalepa, I., and Vetulani, J. 1994b. Reversal by imipramine of beta‐adrenoceptor up‐regulation induced in a chronic mild stress model of depression. Eur. J. Pharmacol. 261:141‐147.
   Papp, M., Klimek, V., and Willner, P. 1994c. Parallel changes in dopamine D‐2 receptor binding in limbic forebrain associated with chronic mild stress‐induced anhedonia and its reversal by imipramine. Psychopharmacology 115:441‐446.
   Papp, M., Moryl, E., and Willner, P. 1996. Pharmacological validation of the chronic mild stress model of depression. Eur. J. Pharmacol. 296:129‐136.
   Papp, M., Gruca, P., Boyer, P‐A., and Mocaër, E. 2003. Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology 28:694‐703.
   Papp, M., Panconi, E., and Gruca, P. 2004. Effects of the novel antidepressant milnacipran in a chronic mild stress model of depression. Drug Dev. Res. 61:101‐106.
   Przegalinski, E., Moryl, E., and Papp, M. 1995. The effect of 5‐HT1A receptor ligands in a chronic mild stress model of depression. Neuropharmacology 34:1305‐1310.
   Sanchez, C., Gruca, P., and Papp, M. 2003. R‐citalopram counteracts the antidepressant‐like effect of escitalopram in a rat chronic mild stress model. Behav. Pharmacol. 14:465‐470.
   Sluzewska, A. and Nowakowska, E. 1994. The effects of carbamazepine, lithium and ketoconazole in chronic mild stress model of depression in rats. Behav. Pharmacol. 5:86.
   Stahl, S.M., Kaiser, L., Roeschen, J., Keppel Hesselink, J.M., and Orazem, J. 1998. Effectiveness of ipsapirone, a 5‐HT‐1A partial agonist, in major depressive disorder: Support for the role of 5‐HT‐1A receptors in the mechanism of action of serotonergic antidepressants. Int. J. Neuropsychopharmacol. 1:11‐18.
   Willner, P., Muscat, R., and Papp, M. 1992. Chronic mild stress‐induced anhedonia: A realistic animal model of depression. Neurosci. Biobehav. Rev. 16:525‐534.
   Willner, P. 1997. Validity, reliability and utility of the chronic mild stress model of depression: A 10‐year review and evaluation. Psychopharmacology 134:319‐329.
   Willner, P. 2005. Chronic mild stress (CMS) revisited: Consistency and behavioural‐neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90‐110.
Key References
   Willner, 2005. See above.
  A detailed review of the validity of CMS‐induced anhedonia as an animal model of depression.
   Willner et al., 1992. See above.
  Description of methodological details and comparison of the CMS procedure with other animal models of depression.
   Papp et al., 2003. See above.
  Demonstrates that the CMS model can be used for both identifying potential novel antidepressants and for discriminating different rates of onset.
   Marston et al., 2010. See above.
  Demonstrates that the CMS model can be used for both identifying second‐generation antipsychotics and for discriminating different rates of onset.
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