Animal Models of Obsessive‐Compulsive Disorder

Jeffrey M. Witkin1

1 Psychiatric Drug Discovery, Neuroscience Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.30
DOI:  10.1002/0471142301.ns0930s45
Online Posting Date:  October, 2008
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Abstract

Obsessive‐compulsive disorder (OCD) occurs with high prevalence, and the drugs used to treat OCD are limited in efficacy and have side‐effect issues. The discovery of improved medicines for OCD has been hampered in part by the lack of predictive in vivo models. This unit provides a brief overview of two methods that might have such predictive utility. Marble burying and nestlet shredding are two behaviors that occur spontaneously with high frequency and repetitiveness in mice. These acute in vivo assays are relatively easy to conduct. Selective serotonin uptake inhibitors decrease these behaviors without producing motor side effects, as assessed by the behavior of walking on a rotating rod. In contrast, some other drugs (e.g., benzodiazepine anxiolytics) only affect marble burying and nestlet shredding at motor‐impairing doses. The present methods might therefore provide one piece of in vivo information for the discovery of novel chemical treatment solutions for the symptoms of OCD. Curr. Protoc. Neurosci. 45:9.30.1‐9.30.9. © 2008 by John Wiley & Sons, Inc.

Keywords: marble burying; nestlet shredding; obsessive‐compulsive disorder; anxiety; SSRI; mice

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Nestlet‐Shredding Model of Obsessive‐Compulsive Disorder in Mice
  • Basic Protocol 2: Marble‐Burying Model of Obsessive‐Compulsive Disorder in Mice
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Nestlet‐Shredding Model of Obsessive‐Compulsive Disorder in Mice

  Materials
  • Test subjects: male, NIH Swiss mice, 4 to 8 weeks of age (weight ∼28 to 35 g); other strains including the full range of genetically engineered mice may be used, although not all have been fully tested
  • Test compound(s) and vehicle
  • Reference compounds: fluoxetine HCl and chlordiazepoxide HCl are reasonable reference standards (available, e.g., from Sigma)
  • Home cages: 24 × 45 × 15–cm mouse cages, in temperature‐controlled vivarium
  • Sawdust bedding (Harlan Sani‐Chips, Harlan‐Teklad)
  • Test room with bench space sufficient to house as many 17 × 28 × 12–cm plastic tubs (test cages) as will be used in one experimental run
  • Rotarod (Ugo Basile model 7650; also see unit 8.12)
  • Balance accurate to 0.1 g
  • Nestlets (multi‐ply gauze nestlet material; Ancare; http://www.ancare.com): 51‐mm‐square × 5‐mm‐thick pieces of cotton fiber, weighing ∼3 g
  • Test cages: clear or opaque plastic tubs (17 × 28 × 12–cm high) with ∼5 mm of sawdust shavings (Harlan Sani‐Chips, Harlan‐Teklad) on the floor
  • Marking pen (for mouse identification)
  • Additional reagents and equipment for assessing motor coordination in rodents using a rotarod (unit 8.12)

Basic Protocol 2: Marble‐Burying Model of Obsessive‐Compulsive Disorder in Mice

  Materials
  • Test subjects: male, NIH Swiss mice 4 to 8 weeks of age (weight ∼28 to 35 g); other strains including the full range of genetically engineered mice may be used, although not all have been fully tested
  • Test compound(s) and vehicle
  • Reference compounds: fluoxetine HCl and chlordiazepoxide HCl are reasonable reference standards (available, e.g., from Sigma)
  • Home cages: 24 × 45 × 15–cm mouse cages, in temperature‐controlled vivarium
  • Sawdust bedding (Harlan Sani‐Chips, Harlan‐Teklad)
  • Test room with bench space sufficient to house as many 17 × 28 × 12–cm high plastic tubs as will be used in one experimental run
  • Rotarod (Ugo Basile model 7650; also see unit 8.12)
  • Mouse test cages: clear or opaque plastic tubs (17 × 28 × 12–cm high) containing 5‐mm sawdust shavings (Harlan Sani‐Chips, Harlan‐Teklad) tamped down by hand
  • Face mask for filtering airborne mouse particulate matter
  • Disposable gloves
  • Blue glass marbles (1.5 cm diameter)
  • Marking pen (for mouse identification)
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Figures

  •   FigureFigure 9.30.1 Comparative effects of chlordiazepoxide and fluoxetine on (A) nestlet shredding, (B) marble burying, and (C) rotarod performance of mice. Open circles represent vehicle control values. Filled circles represent effects of chlordiazepoxide and filled squares represent effects of fluoxetine. Each point represents the effects of data from 6 to 12 mice. * indicates effects significantly different than vehicle control values. Data are adapted from Li et al. () and Rorick‐Kehn et al. ().

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Literature Cited

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   Broekkamp, C.L., Rijk, H.W., Joly‐Gelouin, D., and Lloyd, K.L. 1986. Major tranquilizers can be distinguished from minor tranquilizers on the basis of effects on marble burying and swim‐induced grooming in mice. Eur. J. Pharmacol. 126:223‐229.
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   Kelleher, R.T. and Morse, W.H. 1968. Determinants of the specificity of behavioral effects of drugs. Ergeb. Physiol. 60:1‐56.
   Li, X., Morrow, D., and Witkin, J.M. 2006. Decreases in nestlet shredding of mice by serotonin uptake inhibitors: Comparison with marble burying. Life Sci. 78:1933‐1939.
   Londei, T., Valentini, A.M.V., and Lione, V.G. 1998. Investigative burying by laboratory mice may involve non‐functional compulsive behaviour. Behav. Brain Res. 94:249‐254.
   Martin, J.R., Bös, M., Jenck, F., Moreau, J.‐L., Mutel, V., Sleight, A.J., Wichmann, J., Andrews, J.S., Berendsen, H.H.G., Broekkamp, C.L.E., Ruigt, G.S.F., Köhler, C., and van Delft, A.M.L. 1998. 5‐HT2C receptor agonists: Pharmacological characteristics and therapeutic potential. J. Pharmacol. Exp. Ther. 286:913‐924.
   Nakao, T., Nakagawa, A., Yoshiura, T., Nakatani, E., Nabeyama, M., Yoshizato, C., Kudoh, A., Tada, K., Yoshioka, K., Kawamoto, M., Togao, O., and Kanba, S. 2005. Brain activation of patients with obsessive‐compulsive disorder during neuropsychological and symptom provocation tasks before and after symptom improvement: A functional magnetic resonance imaging study. Biol. Psychiat. 57:901‐910.
   Njung'e, K. and Handley, S.L. 1991. Evaluation of marble‐burying behavior as a model of anxiety. Pharmacol. Biochem. Behav. 38:63‐67.
   Pigott, T.A. and Seay, S. 1998. Biological treatments for obsessive‐compulsive disorder. Literature review. In Obsessive‐Compulsive Disorder: Theory, Research, and Treatment (R.P. Swinson, M.M. Antony, S. Rachman, and M.A. Richter, eds.) pp. 298‐326. Guilford Press, New York.
   Rapoport, J.L. 1988. The neurobiology of obsessive‐compulsive disorder. J. Am. Med. Assoc. 260:2888‐2890.
   Rorick‐Kehn, L.M., Johnson, B.G., Knitowski, K.M., Salhoff, C.R., Witkin, J.M., Perry, K.W., Griffey, K.I., Tizzano, J.P., Monn, J.A., McKinzie, D.L., and Schoepp, D.D. 2007. In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders. Psychopharmacology 193:121‐136.
   Sasson, Y., Zohar, I., Chopra, M., Lustig, M., Iancu, I., and Hendler, T. 1997. Epidemiology of obsessive‐compulsive disorder: A world view. J. Clin. Psychiat. 58:7‐10.
   Welch, J.M., Lu, J., Rodriguiz, R.M., Trotta, N.C., Peca, J., Ding, J.D., Feliciano, C., Chen, M., Adams, J.P., Luo, J., Dudek, S.M., Weinberg, R.J., Calakos, N., Wetsel, W.C., and Feng, G. 2007. Cortico‐striatal synaptic defects and OCD‐like behaviours in Sapap3‐mutant mice. Nature 448:894‐900.
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   Witkin, J.M., Morrow, D., and Li, X. 2004. A rapid experimental conflict procedure for detection of anxiolytic compounds in mice. Psychopharmacology 172:52‐57.
Key References
   Broekkamp et al., 1986. See above.
  First report on the use of marble burying to differentially model antianxiety‐like and antipsychotic‐like effects.
   Li et al., 2006. See above.
  First report on the use of nest material shredding as a potential model predicting drug efficacy in the treatment of anxiety/OCD.
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