Summary

Den tvungne Swim Test som en model af depressive-lignende opførsel

Published: March 02, 2015
doi:

Summary

This protocol describes the forced swim test, which is used for the study of depressive-like behavior in rodents. This procedure involves placing an animal in a container filled with water that eventually will lead to the exhibition of immobility behavior, which is considered to reflect behavioral despair.

Abstract

The goal of the present protocol is to describe the forced swim test (FST), which is one of the most commonly used assays for the study of depressive-like behavior in rodents. The FST is based on the assumption that when placing an animal in a container filled with water, it will first make efforts to escape but eventually will exhibit immobility that may be considered to reflect a measure of behavioral despair. This test has been extensively used because it involves the exposure of the animals to stress, which was shown to have a role in the tendency for major depression. Additionally, the FST has been shown to share some of the factors that are influenced or altered by depression in humans, including changes in food consumption, sleep abnormalities and drug-withdrawal-induced anhedonia. The main advantages of this procedure are that it is relatively easy to perform and that its results are easily and quickly analyzed. Moreover, its sensitivity to a broad range of antidepressant drugs that makes it a suitable screening test is one of the most important features leading to its high predictive validity. Despite its appeal, this model has a number of disadvantages. First, the issue of chronic augmentation is problematic in this test because in real life patients need to be treated for at least several weeks before they experience any relief from their symptoms. Last, due to the aversiveness of the FST, it is important to take into account possible influences it might have on brain structure/function if brain analyses are to be carried out following this procedure.

Introduction

Depression er en livstruende psykiatrisk lidelse og et stort folkesundhedsproblem i hele verden med en incidens på 5% og en levetid på 15-20%. Desuden skønnes det, at i 2020 depression vil være i top tre bidragydere til sygdomsbyrden 1,2. Depression er forbundet med handicap, nedsat livskvalitet, øget sundhedsrelaterede omkostninger og betragtes som en vigtigste risikofaktor for mange sygdomme, herunder hjerte-kar, metaboliske og neuropsykiatriske lidelser 3,4 .Current Farmakoterapeutisk behandlinger har begrænset effekt og er forbundet med mange skadelige bivirkninger 5,6. Derfor er en bedre forståelse af patofysiologien af ​​denne lidelse sideløbende med udviklingen af ​​innovative og forbedrede behandlinger fortsat af afgørende betydning. Derfor dyremodeller er afgørende for at fremme forskning på dette område.

Der er mange modeller, der anvendes til undersøgelse af denne lidelse (<em> fx saccharose præference test, hale suspension test) med test med tvungen svømning (FST, også kendt som Porsolts test efter udvikleren af denne model 7,8) er en af de mest almindeligt anvendte assays 7,9-12.

Under FST et dyr er placeret i en beholder fyldt med vand, hvorfra det ikke kan slippe ud. Dyret vil først forsøge at flygte, men i sidste ende vil udvise immobilitet (dvs. flydende med fraværet af enhver bevægelse bortset fra nødvendigt for at holde næsen oven vande). FST er en meget populær model i dyreforsøg for en række årsager. For det første indebærer eksponering af dyrene til stress, som viste sig at have en rolle i tendensen til større depression 12-14. Desuden depression er ofte ses som en manglende evne til at håndtere stress 15-17. For det andet har vist farmakologisk behandling med antidepressiva før testen for at reducere immobilitet i FST <sup> 18-23. Derfor er det ofte brugt som en screening assay for nye forbindelser med potentielle antidepressive egenskaber 15-17,24. Derudover er FST vist sig at dele nogle af de faktorer, der er påvirket eller ændret af depression hos mennesker, såsom ændringer i fødevareforbruget, søvnforstyrrelser og lægemiddel-tilbagetrækning-induceret anhedonia 15-17,24. Dette er også grunden til, at denne test er undertiden anvendes til at vurdere depressive-lignende adfærd i mutante mus, med stigning eller fald i basal immobilitet (sammenlignet med "vildtype" mus) 25,26.

Protocol

BEMÆRK: Alle forsøgsprotokoller blev godkendt af Den Internationale Komité for Animal Care og brug i Israel. Blev gjort alt for at minimere antallet af anvendte dyr og deres lidelser. 1. Forberedelse af Forced Swim Test Brug to tilstødende værelser. Brug en plads som en "venteværelse" til at holde dyr før adfærdsmæssige test, og den anden til at udføre proceduren. Forbered transparente cylindriske glasbeholdere (den eneste begrænsning for antallet af…

Representative Results

De følgende resultater er baseret på offentliggjorte data fra vores laboratorium. I dette forsøg blev voksen ICR hunmus testet efter 3 ugers behandling med selektive serotonin reuptake inhibitor (SSRI) escitalopram eller en ny urte anti-depressiv og anti-angst behandling (NHT) (for yderligere oplysninger om urte behandling, se 12 , 27,28). One-way ANOVA viste, at behandlingen reducerede depressive-lignende adfærd i FST [F (2,58) = 4,88, p <0,05]. Ensidig Dunnet analyse afslørede, at behandling med ent…

Discussion

FST bruges til at overvåge depressive-lignende adfærd og er baseret på den antagelse, at immobilitet afspejler et mål for adfærdsmæssig fortvivlelse 3. De væsentligste fordele ved denne fremgangsmåde ligger i den relativt nem betjening og hurtige resultater. Desuden dens følsomhed over for en bred vifte af antidepressive lægemidler, der gør det til et egnet screening test er en af de vigtigste funktioner, der fører til den høje prædiktive gyldighed 29. Vigtigt er det, kan denne test o…

Declarações

The authors have nothing to disclose.

Acknowledgements

This research was supported by the Israel Science Foundation (grant No. 738/11), by the National Institute for Psychobiology in Israel (NIPI-7-2011-12), and by the Open University Foundation

Materials

Name of Material/ Equipment Company Catalog Number Comments/Description
Computer Dell intel(r) core(tm) i3-2120 cpu @ 3.30ghz, 4GB ram
Camera VIDO AU-CB422 B/W CCD CAMERA 
http://www.vido-europe.com/products_detail.asp?id=33&pcategory=2
Coding software Biobserve FST Analysis
http://www.biobserve.com/products/fst/index.html
Heating lamp Ikea AA-19025-3 ESPRESSIVIO 400.504.46 - 20W G4 Bulb 
http://www.ikea.com/ms/en_US/customer_service/assembly/E/E00050467.pdf
Heating pillow Sachs EF-188B 38*38cm Heating pillow
http://www.sachs.co.il/eng/lego_tree.php?instance_id=21&actions=show&id=
604

Referências

  1. Levinson, D. F. The genetics of depression: a review. Biological psychiatry. 60, 84-92 (2006).
  2. Murray, C. J., Lopez, A. D. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 349, 1498-1504 (1997).
  3. Cryan, J. F., Holmes, A. The ascent of mouse: advances in modelling human depression and anxiety. Nature reviews. Drug discovery. 4, 775-790 (2005).
  4. Thase, M. E. Managing depressive and anxiety disorders with escitalopram. Expert opinion on pharmacotherapy. 7, 429-440 (2006).
  5. Lam, R. W., Kennedy, S. H. Evidence-based strategies for achieving and sustaining full remission in depression: focus on metaanalyses. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 49, 17S-26S (2004).
  6. Dording, C. M., et al. The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists. Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists. 14, 143-147 (2002).
  7. Porsolt, R. D., Le Pichon, M., Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 266, 730-732 (1977).
  8. Porsolt, R. D., Bertin, A., Jalfre, M. Behavioral despair in mice: a primary screening test for antidepressants. Archives internationales de pharmacodynamie et de therapie. 229, 327-336 (1977).
  9. Cryan, J. F., Markou, A., Lucki, I. Assessing antidepressant activity in rodents: Recent developments and future needs. Trends in Pharmacological Sciences. 23, 238-245 (2002).
  10. Cryan, J. F., et al. Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 101, 8186-8191 (2004).
  11. Porsolt, R. D., Anton, G., Blavet, N., Jalfre, M. Behavioural despair in rats: A new model sensitive to antidepressant treatments. European Journal of Pharmacology. 47, 379-391 (1978).
  12. Doron, R., et al. A novel herbal treatment reduces depressive-like behaviors and increases BDNF levels in the brain of stressed mice. Life sciences. 94, 151-157 (2014).
  13. Caspi, A., et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science. 301, 386-389 (2003).
  14. Kaufman, J., et al. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological psychiatry. 59, 673-680 (2006).
  15. Anisman, H., Zacharko, R. M. Multiple neurochemical and behavioral consequences of stressors: Implications for depression. Pharmacology and Therapeutics. 46, 119-136 (1990).
  16. Kessler, R. C. The effects of stressful life events on depression. Annual Review of Psychology. 48, 191-214 (1997).
  17. Sullivan, P. F., Neale, M. C., Kendler, K. S. Genetic epidemiology of major depression: Review and meta-analysis. American Journal of Psychiatry. 157, 1552-1562 (2000).
  18. Cryan, J. F., Valentino, R. J., Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neuroscience and biobehavioral reviews. 29, 547-569 (2005).
  19. Detke, M. J., Lucki, I. Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: The effects of water depth. Behavioural Brain Research. 73, 43-46 (1996).
  20. Hemby, S. E., et al. Potential antidepressant effects of novel tropane compounds, selective for serotonin or dopamine transporters. Journal of Pharmacology and Experimental Therapeutics. 282, 727-733 (1997).
  21. Bouvard, M., Stinus, L. In the rat forced swimming test, chronic but not subacute administration of dual 5-HT/NA antidepressant treatments may produce greater effects than selective drugs. Behavioural Brain Research. 136, 521-532 (2002).
  22. Page, M. E., Detke, M. J., Dalvi, A., Kirby, L. G., Lucki, I. Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology. 147, 162-167 (1999).
  23. Rubalcava, C., Lucki, I. Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology. 22, 191-199 (2000).
  24. Cryan, J. F., Mombereau, C., Vassout, A. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neuroscience and biobehavioral reviews. 29, 571-625 (2005).
  25. Cryan, J. F., Mombereau, C. In search of a depressed mouse: Utility of models for studying depression-related behavior in genetically modified mice. Molecular Psychiatry. 9, 326-357 (2004).
  26. Sang, K. P., et al. Par-4 links dopamine signaling and depression. Cell. 122, 275-287 (2005).
  27. Doron, R., et al. Anxiolytic effects of a novel herbal treatment in mice models of anxiety. Life sciences. 90, 995-1000 (2012).
  28. Doron, R., et al. Escitalopram or novel herbal mixture treatments during or following exposure to stress reduce anxiety-like behavior through corticosterone and BDNF modifications. PloS one. 9, e91455 (2014).
  29. Borsini, F., Meli, A. Is the forced swimming test a suitable model for revealing antidepressant activity. Psychopharmacology. 94, 147-160 (1988).
  30. Reinhold, J. A., Mandos, L. A., Rickels, K., Lohoff, F. W. Pharmacological treatment of generalized anxiety disorder. Expert opinion on pharmacotherapy. 12, 2457-2467 (2011).
  31. Estrada-Camarena, E., Fernandez-Guasti, A., Lopez-Rubalcava, C. Interaction between estrogens and antidepressants in the forced swimming test in rats. Psychopharmacology. 173, 139-145 (2004).
  32. Weiss, J. M., Kilts, C. D. Animal models of depression and schizophrenia. Textbook of Psychopharmacology. , 89-131 (1998).
  33. Armario, A., Gavaldà, A., Martí, J. Comparison of the behavioural and endocrine response to forced swimming stress in five inbred strains of rats. Psychoneuroendocrinology. 20, 879-890 (1995).
  34. Paré, W. P. Open field, learned helplessness, conditioned defensive burying, and forced-swim tests in WKY rats. Physiology and Behavior. 55, 433-439 (1994).
  35. Overstreet, D. H., Friedman, E., Mathe, A. A., Yadid, G. The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neuroscience and biobehavioral reviews. 29, 739-759 (2005).
  36. Piras, G., Piludu, M. A., Giorgi, O., Corda, M. G. Effects of chronic antidepressant treatments in a putative genetic model of vulnerability (Roman low-avoidance rats) and resistance (Roman high-avoidance rats) to stress-induced depression. Psychopharmacology. 231, 43-53 (2014).
  37. Bielajew, C., et al. Strain and Gender Specific Effects in the Forced Swim Test. Effects of Previous Stress Exposure. Stress. 6, 269-280 (2003).
  38. Fujisaki, C., et al. An immnosuppressive drug, cyclosporine-A acts like anti-depressant for rats under unpredictable chronic stress. Journal of Medical and Dental Sciences. 50, 93-100 (2003).
  39. Gomez, R., Vargas, C. R., Wajner, M., Barros, H. M. T. Lower in vivo brain extracellular GABA concentration in diabetic rats during forced swimming. Brain research. 968, 281-284 (2003).
  40. Hilakivi-Clarke, L. A., Wozniak, K. M., Durcan, M. J., Linnoila, M. Behavior of streptozotocin-diabetic mice in tests of exploration, locomotion, anxiety, depression and aggression. Physiology and Behavior. 48, 429-433 (1990).
  41. Cryan, J. F., Hoyer, D., Markou, A. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biological psychiatry. 54, 49-58 (2003).
  42. Portella, M. J., et al. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. The Journal of clinical psychiatry. 72, 962-969 (2011).
  43. Machado-Vieira, R., Salvadore, G., Luckenbaugh, D. A., Manji, H. K., Zarate, C. A. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. The Journal of clinical psychiatry. 69, 946-958 (2008).
  44. Bordet, R., Thomas, P., Dupuis, B. Effect of pindolol on onset of action of paroxetine in the treatment of major depression: intermediate analysis of a double-blind, placebo-controlled trial. Reseau de Recherche et d’Experimentation Psychopharmacologique. The American journal of psychiatry. 155, 1346-1351 (1998).
  45. Dulawa, S. C., Holick, K. A., Gundersen, B., Hen, R. Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology. 29, 1321-1330 (2004).
  46. Willner, P. Animal models of depression: An overview. Pharmacology and Therapeutics. 45, 425-455 (1990).
  47. Jefferys, D., Funder, J. The effect of water temperature on immobility in the forced swimming test in rats. European Journal of Pharmacology. 253, 91-94 (1994).
  48. West, A. P. Neurobehavioral studies of forced swimming: The role of learning and memory in the forced swim test. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 14, 863-877 (1990).
  49. De Pablo, J. M., Parra, A., Segovia, S., Guillamon, A. Learned immobility explains the behavior of rats in the forced swimming test. Physiology and Behavior. 46, 229-237 (1989).
  50. Dal-Zotto, S., Martí, O., Armario, A. Influence of single or repeated experience of rats with forced swimming on behavioural and physiological responses to the stressor. Behavioural Brain Research. 114, 175-181 (2000).
  51. Rittenhouse, P. A., López-Rubalcava, C., Stanwood, G. D., Lucki, I. Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat. Psychoneuroendocrinology. 27, 303-318 (2002).
  52. Overstreet, D. H., Keeney, A., Hogg, S. Antidepressant effects of citalopram and CRF receptor antagonist CP-154,526 in a rat model of depression. European Journal of Pharmacology. 492, 195-201 (2004).
  53. Chaki, S., et al. MGS0039: A potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology. 46, 457-467 (2004).
  54. Mague, S. D., et al. Antidepressant-like effects of κ-opioid receptor antagonists in the forced swim test in rats. Journal of Pharmacology and Experimental Therapeutics. 305, 323-330 (2003).
  55. Molina-Hernández, M., Téllez-Alcántara, N. P. Antidepressant-like actions of pregnancy, and progesterone in Wistar rats forced to swim. Psychoneuroendocrinology. 26, 479-491 (2001).
  56. Estrada-Camarena, E., Fernández-Guasti, A., López-Rubalcava, C. Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 28, 830-838 (2003).
  57. Gersner, R., Gordon-Kiwkowitz, M., Zangen, A. Automated behavioral analysis of limbs’ activity in the forced swim test. Journal of neuroscience. 180, 82-86 (2009).
  58. Einat, H. Partial effects of the protein kinase C inhibitor chelerythrine in a battery of tests for manic-like behavior in black Swiss mice. Pharmacological reports : PR. 66, 722-725 (2014).
check_url/pt/52587?article_type=t

Play Video

Citar este artigo
Yankelevitch-Yahav, R., Franko, M., Huly, A., Doron, R. The Forced Swim Test as a Model of Depressive-like Behavior. J. Vis. Exp. (97), e52587, doi:10.3791/52587 (2015).

View Video