Animal Models for Anxiety Disorders



Anxiety disorders are characterized by overwhelming anxiety or fear and are chronic and relentless if left untreated. Current available treatments for anxiety disorders are inadequate and some have severe side effects, thus warranting a better understanding of the etiology and mechanisms underlying anxiety and the development of anxiety disorders. In this chapter, the use of animal models to identify molecular and cellular circuitry that regulate fear or anxiety, and the influence of environment on the development of fear or anxiety, are discussed.


Conditioned Stimulus Anxiety Disorder Obsessive Compulsive Disorder Conditioned Suppression Neural Circuitry 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.







Corticotrophin-releasing hormone


Conditioned stimulus


Serotonin 1A receptor


Long-term potentiation


Monoamine oxidase A


Post-traumatic stress disorder


Serotonin reuptake inhibitors


Un-conditioned stimulus


  1. Altemus, M., Glowa, J. R., Galliven, E., Leong, Y. M., Murphy, D. L. (1996). Effects of serotonergic agents on food-restriction-induced hyperactivity. Pharm Biochem Behav 53, 123–131.CrossRefGoogle Scholar
  2. Bale, T. L., Contarino, A., Smith, G. W., Chan, R., Gold, L. H., Sawchenko, P. E., Koob, G. F., Vale, W. W., Lee, K. F. (2000). Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 24, 410–414.PubMedCrossRefGoogle Scholar
  3. Bale, T. L., Picetti, R., Contarino, A., Koob, G. F., Vale, W. W., Lee, K. F. (2002). Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci 22, 193–199.PubMedGoogle Scholar
  4. Bass, S. L., Gerlai, R. (2008). Zebrafish (Danio rerio) responds differentially to stimulus fish: The effects of sympatric and allopatric predators and harmless fish. Behav Brain Res 186, 107–117.PubMedCrossRefGoogle Scholar
  5. Blanchard, D. C., Blanchard, D. C. (1972). Innate and conditioned reactions to threat in rats with amygdaloid lesions. J Comp Physiol Psychol 81, 281–290.PubMedCrossRefGoogle Scholar
  6. Blanchard, R. J., Blanchard, D. C. (1989). Antipredator defensive behaviors in a visible burrow system. J Comp Psychol 103, 70–82.PubMedCrossRefGoogle Scholar
  7. Britton, D. R., Brittone, K. T. (1981). A sensitive open field measure of anxiolytic drug activity. Pharm Biochem Behav 15, 577–582.CrossRefGoogle Scholar
  8. Brown, J. S., Kalish, H. I., Farber, I. E. (1951). Conditioned fear as revealed by magnitude of startle response to an auditory stimulus. J Exp Psychol 41, 317–328.PubMedCrossRefGoogle Scholar
  9. Cases, O., Seif, I., Grimsby, J., Gaspar, P., Chen, K., Pournin, S., Muller, U., Aguet, M., Babinet, C., Shih, J. C. (1995). Aggressive behavior and altered amounts of brain serotonin and norepinerphrine in mice lacking MAOA. Science 268, 1763–1766.PubMedCrossRefGoogle Scholar
  10. Cook, M., Mineka, S., Wolkenstein, B., Laitsch, K. (1985). Observational conditioning of snake fear in unrelated rhesus monkeys. J Abnorm Psychol 94, 591–610.PubMedCrossRefGoogle Scholar
  11. Coste, S. C., Kesterson, R. A., Heldwein, K. A., Stevens, S. L., Heard, A. D., Hollis, J. H., Murray, S. E., Hill, J. K., Pantely, G. A., Hohimer, A. R., . . (2000)Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 24, 403–409.PubMedCrossRefGoogle Scholar
  12. Crawley, J., Goodwin, F. K. (1980). Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav 13, 167–170.PubMedCrossRefGoogle Scholar
  13. Davis, M. (1986). Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm. Behav Neurosci 100, 814–824.PubMedCrossRefGoogle Scholar
  14. Davis, M. (1992). The role of the amygdala in conditioned fear. In The Amygdala: neurobiological aspects of emotion, memory, and mental dysfunction. Wiley-Liss.New York,Google Scholar
  15. Driever, W., Solnica-Krezel, L., Schier, A. F., Neuhauss, S. C. F., Malicki, J., Stemple, D. L., Stainier, D. Y. R., Zwartkruis, F., Abdelilah, S., Rangini, Z., . (1996). A genetic screen for mutations affecting embryogenesis in zebrafish. Development 123, 37–46.PubMedGoogle Scholar
  16. Dunn, A. J., Swiergiel, A. H. (1999). Behaivoral responses to stress are intact in CRF-deficient mice. Brain Res 845, 14–20.PubMedCrossRefGoogle Scholar
  17. Eckart, K., Radulovic, J., Radulovic, M., Jahn, O., Blank, T.,et al. (2002). Pharmacology and biology of corticotropin-releasing factor (CRF) receptors. Recept Channel 8, 163–177.CrossRefGoogle Scholar
  18. Estes, W. K., Skinner, B. F. (1941). Some quantitative properties of anxiety. J Exp Psychol 29, 390–400.CrossRefGoogle Scholar
  19. Fanselow, M. S. (1994). Neural organization of the defensive behavior system responsible for fear. Psychon Bull Rev 1, 429–438.CrossRefGoogle Scholar
  20. File, S. E. (1988). How good is social interaction as a test of anxiety? In Simon, P. SoubrieP. WildlochewrD. Selected models of anxiety, depression, and psychosis., Basel, Karger, pp. 151–166.Google Scholar
  21. File, S. E., Peet, L. A. (1980). The sensitivity of the rat corticosterone response to environmental manipulations and to chronic chlordiazepoxide. Physiol Behav 25, 753–758.PubMedCrossRefGoogle Scholar
  22. Francis, D. D., Szegda, K., Campbell, G., Martin, W. D., Insel, T. R. (2003). Epigenetic sources of behavioral differences in mice. Nat Neurosci 6, 445–446.PubMedGoogle Scholar
  23. Gardner, C. R. (1985). Distress vocalization in rat pups. A simple screeninng method for anxiolytic drugs. J Pharmac Meth 134, 275–283.Google Scholar
  24. Garner, J. P., Dufour, B., Gregg, L. E., Weisker, S. M., Mench, J. A. (2004). Social and husbandry factors affecting the prevalence and severity of barbering (“Whisker trimming”) by laboratory mice. Appl Anim Behav Sci 89, 263–282.CrossRefGoogle Scholar
  25. Gross, C., Zhuang, X., Stark, K., Ramboz, S., Oosting, R., Kirby, L., Santarelli, L., Beck, S., Hen, R. (2002). Serotonin 1A receptor acts during development to establish normal anxiety-like behavior in the adult. Nature 416, 396–400.PubMedCrossRefGoogle Scholar
  26. Guo, S. (2004). Linking genes to brain, behavior, and neurological diseases: what can we learn from zebrafish? Gene Brain Behav 3, 63–74.CrossRefGoogle Scholar
  27. Haffter, P., Granato, M., Brand, M., Mullins, M. C., Hammerschmidt, M., Kane, D. A., Odenthal, J., Van Eeden, F. J. M., Jiang, Y. J., Heisenberg, C. P., . (1996). The identification of genes with unique and essential function in the development of the zebrafish, Danio rerio. Development 123, 1–36.PubMedGoogle Scholar
  28. Heisler, L. K., Chu, H. M., Brennan, T. J., Danao, J. A., Bajwa, P., Parsons, L. H., Tecott, L. H. (1998). Elevated anxiety and anti-depressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci 95, 15049–15054.PubMedCrossRefGoogle Scholar
  29. Joel, D., Avisar, A. (2001). Excessive lever pressing following post-training signal attenuation in rats: a possible animal model of obsessive compulsive disorder? Behav Brain Res 123, 77–87.PubMedCrossRefGoogle Scholar
  30. Kapp, B. S., Whalen, P. J., Supple, W. F., Pascoe, J. P. (1992). Amygdaloid contributions to conditioned arousal and sensory information processing. In The Amygdala: neurobiological aspects of emotion, memory, and mental dysfunction. Wiley-Liss.New York,Google Scholar
  31. Kash, S. F., Tecott, L. H., Hodge, C., Baekkeskov, S. (1999). Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-Kda isoform of glutamic acid decarboxylase. Proc Natl Acad Sci 96, 1698–1703.PubMedCrossRefGoogle Scholar
  32. Kim, J. J., Shih, J. C., Chen, K., Chen, L., Bao, S., Maren, S., Anagnostaras, S. G., Fanselow, M. S., De Maeyer, E., Seif, I., Thompson, R. F. (1997). Selective enhancement of emotional, but not, motor, learning in monoamine oxidase A-deficient mice. Proc Natl Acad Sci 94, 5929–5933.PubMedCrossRefGoogle Scholar
  33. Kishimoto, T., Radulovic, J., Radulovic, M., Lin, C. R., Schrick, C., Hooshmand, F., Hermanson, O., Rosenfeld, M. G., Spiess, J. (2000). Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat Genet 24, 415–419.PubMedCrossRefGoogle Scholar
  34. LeDoux, J. E. (1992). Emotion and the amygdala. In The Amygdala: neurobiological aspects of emotion, memory, and mental dysfunction. Wiley-Liss.New York,Google Scholar
  35. Levin, E. D., Bencan, Z., Cerutti, D. T. (2007). Anxiolytic effects of nicotine in zebrafish. Physiol Behav 90, 54–58.PubMedCrossRefGoogle Scholar
  36. Lister, R. G. (1987). The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92, 180–185.PubMedGoogle Scholar
  37. Lister, R. G., Hilakivi, L. A. (1988). The effects of novelty, isolation, light, and ethanol on the social behavior of mice. Psychopharmacology 96, 181–187.PubMedCrossRefGoogle Scholar
  38. Löw, K., Crestani, F., Keist, R., Benke, D., Brünig, I., Benson, J. A., Fritschy, J. M., Rülicke, T., Bluethmann, H., Möhler, H., Rudolph, U. (2000). Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134.PubMedCrossRefGoogle Scholar
  39. Mendoza, S. P., Smotherman, W. P., Miner, M., Kaplan, J., Leinve, S. (1978). Pituitary-adrenal response to separation in mother and infant squirrel monkeys. Dev Psychobiol 11, 169–175.PubMedCrossRefGoogle Scholar
  40. Miller, D. B., O'Callaghan, J. P. (2002). Neuroendocrine aspects of the response to stress. Metabolism 51, 5–10.PubMedCrossRefGoogle Scholar
  41. Misslin, R., Ropartz, P. (1981). Effects of amygdala lesions on the responses to novelty in mice. Behav Process 6, 329–336.CrossRefGoogle Scholar
  42. Montgomery, K. C. (1955). The relation between fear induced by novel stimulation and exploratory behavior. J Comp Physiol Psychol 48, 254–260.PubMedCrossRefGoogle Scholar
  43. Ninan, P. T. (1982). Benzodiazepine receptor-mediated experimental “anxiety” in primates. Science 218, 1332–1334.PubMedCrossRefGoogle Scholar
  44. Noirot, E. (1972). Ultrasounds and maternal behavior in small rodents. Dev Psychobiol 5, 371–387.PubMedCrossRefGoogle Scholar
  45. Nurnberg, H. G., Keith, S. J., Paxton, D. M. (1997). Consideration of the relevance of ethological animal models for human repetitive behavioral spectrum disorders. Biol Psychiatr 41, 226–229.CrossRefGoogle Scholar
  46. Okon, E. E. (1972). Factors affecting ultrasound production in infant rodents. J Zool Lond 168, 139–148.CrossRefGoogle Scholar
  47. Parks, C. L., Robinson, P. S., Sibille, E., Shenk, T., Toth, M. (1998). Increased anxiety of mice lacking the serotonin 1A receptor. Proc Natl Acad Sci 95, 10734–10739.PubMedCrossRefGoogle Scholar
  48. Pellow, S., Chopin, P., File, S. E., Briley, M. (1985). Validation of open/closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth 14, 149–167.CrossRefGoogle Scholar
  49. Preil, J., Müller, M. B., Gesing, A., Reul, J. M., Sillaber, I., van Gaalen, M. M., Landgrebe, J., Holsboer, F., Stenzel-Poore, M., Wurst, W. (2001). Regulation of the hypothalamic-pituitary-adrenocortical system in mice deficient for CRH receptors 1 and 2. Endocrinology 142, 4946–4955.PubMedCrossRefGoogle Scholar
  50. Ramboz, S., Oosting, R., Amara, D. A., Kung, H. F., Blier, P., Mendelsohn, M., Mann, J. J., Brunner, D., Hen, R. (1998). Serotonin 1A receptor knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci 95, 14476–14481.PubMedCrossRefGoogle Scholar
  51. Smith, S. M. (1975). Innate recognition of coral snake pattern by a possible avian predator. Science 187, 759–760.PubMedCrossRefGoogle Scholar
  52. Smith, S. M. (1977). Coral snake recognition and stimulus generalization by naive great kiskadees. Nature 265, 535–536.CrossRefGoogle Scholar
  53. Smith, G. W., Aubry, J. M., Dellu, F., Contarino, A., Bilezikjian, L. M., (1998)Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20, 1093–1102.PubMedCrossRefGoogle Scholar
  54. Speedie , N., and Gerlai, R. (2007). Alarm substance induced behavioral responses in zebrafish (Danio rerio). Behav Brain Res [Epub ahead of print].<bib id="bib54_9"> <otherref>Speedie, N., and Gerlai, R. (2007). Alarm substance induced behavioral responses in zebrafish (Danio rerio). Behav Brain Res <Emphasis Type="Italic">[Epub ahead of print]</Emphasis>.</otherref> </bib> Google Scholar
  55. Stenzel-poore, M. P., Heinrichs, S. C., Rivest, S., Koob, G. F., Vale, W. W. (1994). overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J Neurosci 14, 2579–2584.PubMedGoogle Scholar
  56. Timpl, P., Spanagel, R., Sillaber, I., Kresse, A., Reul, J. M., (1998). Impaired stress response and reduced anxiety in mice lacking functional corticotropin-releasing hormone receptor 1. Nat Genet 19, 162–, e.PubMedCrossRefGoogle Scholar
  57. Treit, D. (1985). The inhibitory effect of diazepam on defensive burying: anxiolytic vs. analgesic effects. Pharm Biochem Behav 22, 47–52.CrossRefGoogle Scholar
  58. Vaughan, J., Donaldson, C., Bittencourt, J., Perrin, M. H., Lewis, K., and al., e(1995). Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378, 287–292.PubMedCrossRefGoogle Scholar
  59. Walsh, R. N., Cummins, R. A. (1976). The open field test: a critical review. Psychol Bull 83, 482–504.PubMedCrossRefGoogle Scholar
  60. Willner, P. (1984). The validity of animal models of depression. Psychopharmacology 83, 1–16.PubMedCrossRefGoogle Scholar
  61. Zon, L. I., Peterson, R. T. (2005). In vivo drug discovery in the zebrafish. Nat Rev Drug Discovery 4, 35–44.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Biopharmaceutical Sciences, Programs in Human Genetics and Biological SciencesUniversity of CaliforniaSan FranciscoUSA

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