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Promises and Limitations of Transgenic and Knockout Mice in Modeling Psychiatric Symptoms

  • Andrew Holmes
  • Jacqueline N. Crawley
Part of the Neurobiological Foundation of Aberrant Behaviors book series (NFAB, volume 1)

Abstract

Targeted gene mutation provides a powerful tool for dissecting the biological substrates of neuropsychiatric diseases. Transgenic mice contain a new gene, such as the human gene for a disease, or an extra copy of a normal mouse gene. Knockout mice contain a DNA construct that effectively deletes a gene from the mouse genome. The targeted gene mutation approach is particularly useful for testing discrete hypotheses about genes linked to major psychiatric syndromes. Neurochemical, anatomical, neurophysiological, and behavioral sequelae of the mutation of a homologous gene in mice are compared to the symptoms characterizing the human disease state (Burright et al., 1997; Campbell and Gold, 1996; Crawley, 1999, 2000; Crawley and Paylor, 1997; Crawley et al., 1997; Jucker and Ingram, 1997; Kieffer, 1999; Nelson and Young, 1997; Picciotto, 1999).

Keywords

Open Field Corticotropin Release Factor Prepulse Inhibition Receptor Knockout Mouse Morris Water Task 
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.

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References

  1. Accili, D., Fishburn, C.S., Drago, J., Steiner, H., Lachowicz, J., Park, R.H., Gauda, E.B., Lee, E.J., Cool, M.H., Sibley, D.R., Gerfen, C.R., Westphal, H., Fuchs, S. (1996) A targeted mutation of the D, dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci USA. 93: 1945–1949.PubMedGoogle Scholar
  2. American Psychiatric Association (1994) DSM-IV: Diagnostic and statistical manual of mental disorders. Fourth edition, Washington, DC: American Psychiatric Association.Google Scholar
  3. Applegate, C.D. and Tecott, L.H. (1998) Global increases in seizure susceptibility in mice lacking 5HT2C receptors: a behavioral analysis. Exp Neurol. 154: 522–530.PubMedGoogle Scholar
  4. Balk, J.H., Picetti, R., Salardi, A., Thirlet, G., Dierich, A., Depaulis, A., Le Meur, M., Borrelli, E. (1995) Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature. 377: 424–428.Google Scholar
  5. Banbury Conference on Genetic Background in Mice. (1997): Neuron. 19: 755–759.Google Scholar
  6. Barnard, E.A., Skolnick, P., Olsen, R.W., Mohler, H., Sieghart, W., Biggio, G., Braestrup, C., Bateson, A.N., Langer, S.Z. (1998) International Union of Pharmacology. XV. Subtypes of gammaaminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev. 50: 291–313.PubMedGoogle Scholar
  7. Barnett, S.A. (1963) The Rat: A Study in Behavior. London: Methuen.Google Scholar
  8. Belzung, C. and Le Pape, G. (1994) Comparison of different behavioral test situations used in psychopharmacology for measurement of anxiety. Physiol Behay. 56: 623–628.Google Scholar
  9. Bengel, D., Murphy, D.L., Andrews, A.M., Wichems, C.H., Feltner, D., Heils, A., Mossner, R., Westphal, H., Lesch, K.P. (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (“ecstasy”) in serotonin transporter-deficient mice. Mol Pharm. 53: 649–655.Google Scholar
  10. Beuzen, A. and Belzung, C. (1995) Link between emotional memory and anxiety states: a study by principal component analysis. Physiol Behay. 58: 111–118.Google Scholar
  11. Blanchard, D.C., Blanchard, R.J., Tom, P., Rodgers, R.J. (1990) Diazepam changes risk assessment in an anxiety/defense test battery. Psychopharmacology. 101: 511–518.PubMedGoogle Scholar
  12. Blanchard, R.J., Hebert, M.A., Ferrari, P., Palanza, P., Figueira, R., Blanchard, D.C., Parmigiani, S. (1998) Defensive behaviors in wild and laboratory (Swiss) mice: the mouse defense test battery. Physiol Behay. 65: 201–209.Google Scholar
  13. Boulay, D., Depoortere, R., Rostene, W., Perrault, G., Sanger, D.J. (1999) Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice. Neuropharmacology. 38: 555–565.PubMedGoogle Scholar
  14. Britton, K.T., Lee, G., Dana, R., Risch, S.C., and Koob, G.F. (1986) Activating and `anxiogenic’ effects of corticotropin releasing factor are not inhibited by blockade of the pituitary-adrenal system with dexamethasone. Life Sci. 39: 1281–1286.PubMedGoogle Scholar
  15. Brunner, D., Buhot, M.C., Hen, R., Hofer, M. (1999) Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. Behav Neurosci. 113: 587–601.PubMedGoogle Scholar
  16. Burright, E.N., Orr, H.T., andClark, H.B. (1997) Mouse models of human CAG repeat disorders. Brain Pathol. 7: 965–977.PubMedGoogle Scholar
  17. Campbell, I.L. and Gold, L.H. (1996) Transgenic modeling of neuropsychiatric disorders. Mol. Psychiatry. 1: 105–120.PubMedGoogle Scholar
  18. Campbell, K.M., de Lecea, L., Severynse, D.M., Caron, M.G., McGrath, M.J., Sparber, S.B., Sun, L.Y., and Burton, F.H. (1999) OCD-Like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons. J Neurosci. 19: 5044–5053.PubMedGoogle Scholar
  19. Cases, O., Seif, I., Grimsby, J., Gaspar, P., Chen, K., Pournin, S., Muller, U., Aguet, M., Babinet, C., Shih, J.C., and De Maeyer, E. (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science. 268: 1763–1766.PubMedGoogle Scholar
  20. Chen, R., Lewis, K.A., Perrin, M.H., Vale, W.W. (1993) Expression cloning of a human corticotropinreleasing-factor receptor. Proc Natl Acad Sci U S A. 90: 8967–8971.PubMedGoogle Scholar
  21. Chen, C., Rainnie, D.G., Greene, R.W., and Tonegawa, S. (1994) Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II. Science. 266: 291–294.PubMedGoogle Scholar
  22. Christmas, A.J. and Maxwell, D.R. (1970) A comparison of the effects of some benzodiazepines and other drugs on aggressive and exploratory behaviour in mice and rats. Neuropharmacology. 9: 17–29.PubMedGoogle Scholar
  23. Cole, J.C., Burroughs, G.J., Laverty, C.R., Sheriff, N.C., Sparham, E.A., Rodgers, R.J. (1995) Anxiolytic-like effects of yohimbine in the murine plus-maze: strain independence and evidence against alpha 2-adrenoceptor mediation. Psychopharmacology. 118: 425–436.PubMedGoogle Scholar
  24. Contarino, A., Dellu, F., Koob, G.F., Smith, G.W., Lee, K.F., Vale, W., Gold, L.H. (1999) Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Res. 835: 1–9.PubMedGoogle Scholar
  25. Costall, B., Hendrie, C.A., Kelly, M.E., Naylor, R.J. (1987) Actions of sulpiride and tiapride in a simple model of anxiety in mice. Neuropharmacology. 26: 195–200.PubMedGoogle Scholar
  26. Crabbe, J.C., Wahlsten, D., Dudek, B.C. (1999) Genetics of mouse behavior: interactions with laboratory environment. Science. 284: 1670–1672.PubMedGoogle Scholar
  27. Crawley, J.N. (1981) Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines. Pharmacol Biochem Behay. 15: 695–699.Google Scholar
  28. Crawley, J.N. (1985) Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev. 9: 37–44.PubMedGoogle Scholar
  29. Crawley, J.N. (1996) Unusual behavioral phenotypes of inbred mouse strains. Trends Neurosci. 19: 181–182.PubMedGoogle Scholar
  30. Crawley, J.N. (1999) Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functionss, motor abilities, and specific behavioral tests. Brain Res. 835: 18–26.PubMedGoogle Scholar
  31. Crawley, J.N. (2000) What’s Wrong With My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice. New York: John Wiley and Sons, Inc.Google Scholar
  32. Crawley, J.N., Belknap, J.K., Collins, A., Crabbe, J.C., Frankel, W., Henderson, N., Hitzemann, R.J., Maxson, S.C., Miner, L.L., Silva, A.J., Wehner, J.M., Wynshaw-Boris, A., and Paylor, R. (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology. 132: 107–124.PubMedGoogle Scholar
  33. Crawley, J.N. and Davis, L.G. (1982) Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains. Brain Res Bull. 8: 609–612.PubMedGoogle Scholar
  34. Crawley, J.N., Gerfen, C., McKay, R., Rogawski, M.A., Sibley, D.R., and Skolnick, P. (1999) Current Procotols in Neuroscience. New York: John Wiley and Sons, Inc.Google Scholar
  35. Crawley, J. and Goodwin, F.K. (1980) Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behay. 13: 167–170.Google Scholar
  36. Crawley, J.N. and Paylor, R. (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Hormones Behay. 31: 197–211.Google Scholar
  37. Crestani, F., Lorez, M., Baer, K., Essrich, C., Benke, D., Laurent, J.P., Belzung, C., Fritschy, J.M., Luscher, B., and Mohler, H. (1999) Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci. 2: 833–839.PubMedGoogle Scholar
  38. Dawson, G.R. and Tricklebank, M.D. (1995) Use of the elevated plus maze in the search for novel anxiolytic agents. Trends Pharmacol Sci. 16: 33–36.PubMedGoogle Scholar
  39. De Vry, J. (1995) HT1A receptor agonists: recent developments and controversial issues. Psychopharmacology. 121: 1–26.PubMedGoogle Scholar
  40. Drago, F., Contarino, A., Busa, L. (1999) The expression of neuropeptide-induced excessive grooming behavior in dopamine DI and D2 receptor-deficient mice. Europ J Pharmacol. 365: 125–131.Google Scholar
  41. Dulawa, S.C., Grandy, D.K., Low, M.J., Paulus, M.P., Geyer, M.A. (1999) Dopamine D4 receptorknockout mice exhibit reduced exploration of novel stimuli. J Neurosci. 19: 9550–9556.PubMedGoogle Scholar
  42. Dulawa, S.C., Hen, R., Scearce-Levie, K., Geyer, M.A. (1997) Serotonin 1B receptor modulation of startle reactivity, habituation, and prepulse inhibition in wild-type and serotonin 1B knockout mice. Psychopharmacology. 132: 125–134.PubMedGoogle Scholar
  43. Ellinbroek, B.A. and Cools, A.R. (1990) Animal models with construct validity for schizophrenia. Behav Pharmacol. 1: 469–490.Google Scholar
  44. Falls, W.A., Carlson, S., Turner, J.G., Willott, J.F. (1997) Fear-potentiated startle in two strains of inbred mice. Behav Neurosc. 111: 855–861.Google Scholar
  45. Fernandes, C. and File, S.E. (1996) The influence of open arm ledges and maze experience in the elevated plus-maze. Pharmacol Biochem Behay. 54: 31–40.Google Scholar
  46. File, S.E. (1993) The interplay of learning and anxiety in the elevated plus-maze. Behav Brain Res. 58: 199–202.PubMedGoogle Scholar
  47. File, S.E., Gonzalez, L.E., Gallant, R. (1999) Role of the dorsomedial hypothalamus in mediating the response to benzodiazepines on trial 2 in the elevated plus-maze test of anxiety. Neuropsychopharmacology. 21: 312–320.PubMedGoogle Scholar
  48. File, S.E. and Hyde, J.R. (1978) Can social interaction be used to measure anxiety? Br J Pharmacol. 62: 19–24.PubMedGoogle Scholar
  49. File, S.E., Zangrossi, H., Viana, M., Graeff, F.G. (1993) Trial 2 in the elevated plus-maze: a different form of fear? Psychopharmacology. 11: 491–494.Google Scholar
  50. Flint, J., Corley, R., DeFries, J.C., Fulker, D.W., Gray, J.A., Miller, S., Collins, A.C. (1995) A simple genetic basis for a complex psychological trait in laboratory mice. Science. 8: 1432–1435.Google Scholar
  51. Gerlai, R. (1996) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci. 19: 177–181.PubMedGoogle Scholar
  52. Gingrich, J.R. and Roder, J. (1998) Inducible gene expression in the nervous system of transgenic mice. Ann Rev Neurosci. 21: 377–405.PubMedGoogle Scholar
  53. Giros, B., Jaber, M., Jones, S.R., Wightman, R.M., Caron, M.G. (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 379: 606–612.PubMedGoogle Scholar
  54. Glue, P., Wilson, S., Coupland, N., Ball., D., Nutt, D.J. (1995) The relationship between benzodiazepine sensitivity and neuroticism. J Anxiety Disord. 9: 33–45.Google Scholar
  55. Gogos, J.A., Morgan, M., Luine, V., Santha, M., Ogawa, S., Pfaff, D., Karayiorgou, M. (1998) Catechol0-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA. 95: 9991–9996.PubMedGoogle Scholar
  56. Grailhe, R., Waeber, C., Dulawa, S.C., Hornung, J.P., Zhuang, X., Brunner, D., Geyer, M.A. and Hen, R. (1999) Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor. Neuron. 22: 581–591.PubMedGoogle Scholar
  57. Gray, J.A. (1979) Emotionality in male and female rodents: reply to Archer. Br J Psychol. 70: 425–440.PubMedGoogle Scholar
  58. Griebel, G. (1995) 5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research. Pharmacol Ther. 65: 319–95.Google Scholar
  59. Griebel, G., Blanchard, D.C., Jung, A., Lee, J.C., Masuda, C.K. and Blanchard, R.J. (1995) Further evidence that the mouse defense test battery is useful for screening anxiolytic and panicolytic drugs: effects of acute and chronic treatment with alprazolam. Neuropharmacology. 34: 1625–1633.PubMedGoogle Scholar
  60. Griebel, G., Belzung, C., Misslin, R., Vogel, E. (1993) The free-exploratory paradigm: an effective method for measuring neophobic behaviour in mice and testing potential neophobia-reducing drugs. Behav Pharm. 4: 637–644.Google Scholar
  61. Griebel, G., Perrault, G., Sanger, D.J. (1998) Limited anxiolytic-like effects of non-benzodiazepine hypnotics in rodents. J Psychopharmacol. 12: 356–365.PubMedGoogle Scholar
  62. Griebel, G., Rodgers, R.J., Perrault, G., Sanger, D.J. (1997) Risk assessment behaviour: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test. Pharmacol Biochem Behay. 57: 817–827.Google Scholar
  63. Grimsby, J., Toth, M., Chen, K., Kumazawa, T., Klaidman, L., Adams, J.D., Karoum, F., Gal, J., Shih, J.C. (1997) Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nat Genet. 17: 206–210.PubMedGoogle Scholar
  64. Grossen, N.E. and Kelley, M.J. (1972) Species-specific behavior and acquisition of avoidance behavior in rats. J Comp Physiol Psychol. 81: 307–310.PubMedGoogle Scholar
  65. Gunther, U., Benson, J., Benke, D., Fritschy, J.M., Reyes, G., Knoflach, F., Crestani, F., Aguzzi, A., Arigoni, M., Lang, Y., Bluethman, H., Mohler, H, Luscher, B. (1995). Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A. 92: 7749–7753.PubMedGoogle Scholar
  66. Haefely, W., Martin, J.R., Schoch, P. (1990) Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Sci. 11: 452–456.PubMedGoogle Scholar
  67. Hall, C.S. (1936) Emotional behavior in the rat. I Defecation and urination as measures of individual differences in emotionality. J. Comp Psychol. 18: 385–403.Google Scholar
  68. Handley, S.L. and Mithani, S. (1984) Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of `fear’-motivated behaviour. Naunyn Schmiedebergs Arch Pharmacol. 327: 1–5.PubMedGoogle Scholar
  69. Heinrichs, S.C., Min, H., Tamraz, S., Carmouche, M., Boehme, S.A., Vale, W.W. (1997) Anti-sexual and anxiogenic behavioral consequences of corticotropin-releasing factor overexpression are centrally mediated. Psychoneuroendocrinology. 22: 215–224.PubMedGoogle Scholar
  70. Heisler, L.K., Chu, H.M., Brennan, T.J., Danao, J.A., Bajwa, P., Parsons, L.H., Tecott, L.H. (1998) Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A. 95: 15049–15054.PubMedGoogle Scholar
  71. Hogg, S. (1996) A review of the validity and variability of the elevated plus-maze as an animal model of anxiety Pharmacol Biochem Behay. 54: 21–30.Google Scholar
  72. Holmes, A. and Rodgers, R.J. (1998) Responses of Swiss-Webster mice to repeated plus-maze experience: further evidence for a qualitative shift in emotional state? Pharmacol Biochem Behay. 60: 473–488.Google Scholar
  73. Holmes, A. and Rodgers, R.J. (1999) Influence of spatial and temporal manipulations on the anxiolytic efficacy of chlordiazepoxide in mice previously exposed to the elevated plus-maze. Neurosci Biobehav Rev. 23: 971–908.PubMedGoogle Scholar
  74. Homanics, G.E., Harrison, N.L., Quinlan, J.J., Krasowski, M.D., Rick, C.E., de Blas, A.L., Mehta, A.K., Kist, F., Mihalek, R.M., Aul, J.J., Firestone, L.L. (1999a) Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the gamma2 subunit of the gamma-aminobutyrate type A receptor. Neuropharmacology. 38: 253–265.PubMedGoogle Scholar
  75. Homanics, G.E., Quinlan, J.J., Firestone, L.L. (1999b) Pharmacologic and behavioral responses of inbred C57BL/6J and strain 129/SvJ mouse lines. Pharmacol Biochem Behay. 63: 21–26.Google Scholar
  76. Irwin, S. (1968) Comprehensive observational assessment: la. A systematic, quantitative procedure for assessing the behavioural and physiologic state of the mouse. Psychopharmacologia. 13: 222–257.PubMedGoogle Scholar
  77. Iversen, S.D. (1984) 5-HT and anxiety. Neuropharmacology. 23: 1553–1560.Google Scholar
  78. Jucker, M. and Ingram, D.K. (1997) Murine models of brain aging and age-related neurodegenerative diseases. Behav Brain Res. 85: 1–25.PubMedGoogle Scholar
  79. Kalivas, P.W. (1995) Interactions between dopamine and excitatory amino acids in behavioral sensitization to psychostimulants. Drug Alc Depend. 37: 95–100.Google Scholar
  80. Kash, S.F., Tecott, L.H., Hodge, C. and 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 USA. 96: 1698–1703.PubMedGoogle Scholar
  81. Kieffer, B.L. (1999) Opioids: first lessons from knockout mice. Trends Pharmacol Sci. 20: 19–26.PubMedGoogle Scholar
  82. 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 U S A. 94: 5929–5933.PubMedGoogle Scholar
  83. Koster, A., Montkowski, A., Schulz, S., Stube, E.M., Knaudt, K., Jenck, F., Moreau, J.L., Nothacker, H.P., Civelli, O., Reinscheid, R.K. (1999) Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice. Proc Natl Acad Sci U S A. 96: 10444–10449.PubMedGoogle Scholar
  84. Kuczenski, R. and Segal, D.S. (1999) Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate. Psychopharmacology. 147: 96–103.PubMedGoogle Scholar
  85. Lesch, K.P., Bengel, D., Heils, A., Sabol, S.Z., Greenberg, B.D., Petri, S., Benjamin, J., Muller, C.R., Hamer, D.H., Murphy, D.L. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 274: 1527–1531.PubMedGoogle Scholar
  86. Liebowitz, M.R. (1999) Update on the diagnosis and treatment of social anxiety disorder. J Clin Psychiatry. 18: 22–26.Google Scholar
  87. Liebowitz, M.R., Hollander, E., Schneier, F., Campeas, R., Welkowitz, L., Hatterer, J., Fallon, B. (1990) Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders. Acta Psychiatr Scand. 360: 29–34.Google Scholar
  88. Liebsch, G., Landgraf, R., Gerstberger, R., Probst, J.C., Wotjak, C.T., Engelmann, M., Holsboer, F., Montkowski, A. (1995) Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats. Regul Pept. 59: 229–239.PubMedGoogle Scholar
  89. Lijam, N., Paylor, R., McDonald, M.P., Crawley, J.N., Deng, C.X., Herrup, K., Stevens, K.E., Maccaferri, G., McBain, C.J., Sussman, D.J., Wynshaw-Boris, A. (1997) Social interaction and sensorimotor gating abnormalities in mice lacking Dvll. Cell. 90: 895–905.PubMedGoogle Scholar
  90. Lister, R.G. (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology. 92: 180–185.PubMedGoogle Scholar
  91. Lister, R.G. (1990) Ethologically-based animal models of anxiety disorders. Pharmacol Ther. 46: 321–40.PubMedGoogle Scholar
  92. Livy, D.J. and Wahlsten, D. (1997) Retarded formation of the hippocampal commissure in embryos from mouse strains lacking a corpus callosum. Hippocampus. 7: 2–14.PubMedGoogle Scholar
  93. Maldonado, R., Saiardi., A., Valverde, O., Samad, T. A., Roques, B. P., Borrelli, E. (1997) Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388: 586–589.PubMedGoogle Scholar
  94. Malleret, G., Hen, R., Guillou, J.L., Segu, L. and Buhot, M.C. (1999) 5-HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze. J Neurosci. 19: 6157–6168.Google Scholar
  95. Markel, P., Shu, P., Ebeling, C., Carlson, G.A., Nagle, D.L., Smutko, J.S. and Moore, K.J. (1997) Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nature Genetics. 17: 280–284.PubMedGoogle Scholar
  96. Mathis, C., Neuman, P. E., Gershenfeld, H., Paul, S. M., Crawley, J. N. (1995) Genetic analysis of anxiety-related drugs in AXB and BXA recombinant inbred mouse strains. Behay. Genet. 25: 557–568.Google Scholar
  97. Mathis, C., Paul, S.M., Crawley, J.N. (1994) Characterization of benzodiazepine-sensitive behaviors in the A/J and C57BL/6J inbred strains of mice. Behav Genet. 24: 171–180.PubMedGoogle Scholar
  98. Miczek, K.A., Weerts, E.M., Vivian, J.A., Barros, H.M. (1995) Aggression, anxiety and vocalizations in animals: GABAA and 5-HT anxiolytics. Psychopharmacology. 121: 38–56.PubMedGoogle Scholar
  99. Mihalek, R.M., Banerjee, P.K., Korpi, E.R., Quinlan, J.J., Firestone, L.L., Mi, Z.P., Lagenaur, C., Tretter, V., Sieghart, W., Anagnostaras, S.G., Sage, J.R., Fanselow, M.S., Guidotti, A., Spigelman, I., Li, Z., DeLorey, T.M., Olsen, R.W., Homanics, G.E. (1999) Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Nati Acad Sci U S A. 96: 12905–12910.Google Scholar
  100. Montgomery, K.C. (1955). The relation between fear induced by novel stimulation and exploratory behaviour. J Comp Physiol Psychol. 48: 254–260.PubMedGoogle Scholar
  101. Montkowski, A., Poettig, M., Mederer, A., Holsboer, F. (1997) Behavioural performance in three substrains of mouse strain 129. Brain Res. 762: 12–18.PubMedGoogle Scholar
  102. Moser, V.C., Cheek, B.M., MacPhail, R.C. (1995) A multidisciplinary approach to toxicological screening: III. Neurobehavioral toxicity. J Toxicol Environ Health. 45: 173–210.Google Scholar
  103. Murphy, D.L., Mueller, E.A., Hill, J.L., Tolliver, T.J., Jacobsen, F.M. (1989) Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers. Psychopharmacology. 98: 275–282.PubMedGoogle Scholar
  104. Murphy, D.L., Wichems, C., Li, Q., Heils, A. (1999) Molecular manipulations as tools for enhancing our understanding of 5-HT neurotransmission. Trends Pharmacol Sci. 20: 246–252.PubMedGoogle Scholar
  105. Nelson, R.J., Demas, G.E., Huang, P.L., Fishman, M.C., Dawson, V.L., Dawson, T.M., Synder, S.H. (1995) Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase. Nature. 378: 383–386.PubMedGoogle Scholar
  106. Nelson, R.J. and Young, K.A. (1998) Behavior in mice with targeted disruption of single genes. Neurosci Biobehav Rev. 22: 453–462.PubMedGoogle Scholar
  107. O’Donovan, M.C. and Owen, M.H. (1999) Candidate-gene association studies of schizophrenia. Am J Human Genetics. 65: 587–592.Google Scholar
  108. Olivier, B., Molewijk, E., van Oorschot, R., van der Poel, G., Zethof, T., van der Heyden, J., Mos, J. (1994) New animal models of anxiety. Eur Neuropsychopharmacol. 4: 93–102.PubMedGoogle Scholar
  109. Ongini, E., Iuliano, E., Racagni, G. (1982) Cerebellar cyclic GMP and behavioral effects after acute and repeated administration of benzodiazepines in mice. Eur J Pharmacol. 80: 185–90.PubMedGoogle Scholar
  110. Parks, C.L., Robinson, P.S., Sibille, E., Shenk, T., Toth, M. (1998) Increased anxiety of mice lacking the serotoninlA receptor. Proc Natl Acad Sci USA. 95: 10734–10739.PubMedGoogle Scholar
  111. Paulus, M.P., Dulawa, S.C., Ralph, R.J., Geyer, M.A. (1999) Behavioral organization is independent of locomotor activity in 129 and C57 mouse strains. Brain Res. 835: 27–36.PubMedGoogle Scholar
  112. Paylor, R., Nguyen, M., Crawley, J.N., Patrick, J., Beaudet, A., Orr-Urtreger, A. (1998) ca nicotinic receptor subunits are not necessary for hippocampal-dependent learning or sensorimotor gating: A behavioral characterization ofAcra7-deficient mice. Learning and Memory. 5: 302–316.Google Scholar
  113. 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 Methods. 14: 149–167.PubMedGoogle Scholar
  114. Petitto, J.M., McNamara, R.K., Gendreau, P.L., Huang, Z., Jackson, A.J. (1999) Impaired learning and memory and altered hippocampal neurodevelopment resulting from interleukin-2 gene deletion. J Neurosci Res. 56: 441–446.PubMedGoogle Scholar
  115. Picciotto, M.R. (1999) Knock-out mouse models used to study neurobiological systems. Critical Reviews Neurobiol. 13: 103–149.Google Scholar
  116. Ralph, R.J., Varty, G.B., Kelly, M.A., Wang, Y.M., Caron, M.G., Rubinstein, M., Grandy, D.K., Low, M.J., Geyer, M.A. (1999) The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci. 19: 4627–4633Google Scholar
  117. Ramboz, S., Oosting, R., Amara, D.A., Kung, H.F., Blier, P., Mendelsohn, M., Mann, J.J., Brunner, D., Hen, R. (1998) Serotonin receptor IA knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci USA. 95: 14476–14481.PubMedGoogle Scholar
  118. Ramboz, S., Saudou, F., Amara, D.A., Belzung, C., Segu, L., Misslin, R., Buhot, M.C., Hen, R. (1996) 5HTIB receptor knock out–behavioral consequences. Behav Brain Res. 73: 305–312.Google Scholar
  119. Rodgers, R.J. (1997) Animal models of `anxiety’: where next? Behav Pharmacol. 8: 477–496.PubMedGoogle Scholar
  120. Rodgers, R.J., Cole, J.C. (1993) Influence of social isolation, gender, strain, and prior novelty on plus-maze behaviour in mice. Physiol Behay. 54: 729–736.Google Scholar
  121. Rodgers, R.J. Haller, J., Holmes, A., Halasz, J., Walton, T.J., Brain, P.F. (1999) Corticosterone response to the plus-maze: high correlation with risk assessment in rats and mice. Physiol Behay. in press.Google Scholar
  122. Rogers, D.C., Fisher, E.M.C., Brown, S.D.M., Peters, J., Hunter, A.J., Martin, J.E. (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mammalian Genome. 8: 711–713.Google Scholar
  123. Rubenstein, M., Phillips, T.J., Bunzow, J.R., Falzone, T.L., Dziewczapolski, G., Zhang, G., Fang, Y., Larson, J.L., McDougall, J.A., Chester, J.A., Saez, C., Pugsley, T.A., Gershanik, O., Low, M.J., Grandy, D.K. (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell. 90: 991–1001.Google Scholar
  124. Rudolph, U., Crestani, F., Benke, D., Brunig, I., Benson, J.A., Fritschy, J.M., Martin, J.R., Bluethmann, H., Mohler, H. (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 401: 796–800.PubMedGoogle Scholar
  125. Sallinen, J., Haapalinna, A., Viitamaa, T., Kobilka, B.K., Scheinin, M. (1998) Adrenergic alpha2Creceptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice. J Neurosci. 18: 3035–3042.PubMedGoogle Scholar
  126. Sams-Dodd, F., Lipska, B.K., Weinberger, D. (1997) Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood. Psychopharmacology. 132: 303–310.PubMedGoogle Scholar
  127. Shepherd, J.K., Grewal, S.S., Fletcher, A., Bill, D.J., Dourish, C.T. (1994) Behavioural and pharmacological characterisation of the elevated “zero-maze” as an animal model of anxiety. Psychopharmacology. 116: 56–64.PubMedGoogle Scholar
  128. Sibley, D.R., Hollon, T.R., Gleason, T.C., Lachowicz, J.E., Ariano, M.A., Huang, S.P., Westphal, H., Surmeier, D.J., Crawley, J.N. (1998) Generation and characterization of Ds dopamine receptor knock-out mice. American College of Neuropsychopharmacology 376’ Annual Meeting. Abstract 56: page 287.Google Scholar
  129. Silver, L. (1995) Mouse Genetics: Concepts and Applications. New York: Oxford University Press.Google Scholar
  130. Sluyter, F., Korte, S.M., Bohus, B., Van Oortmerssen, G.A. (1996) Behavioral stress response of genetically selected aggressive and nonaggressive wild house mice in the shock-probe/defensive burying test. Pharmacol Biochem Behay. 54: 113–116.Google Scholar
  131. Smith, D.R., Striplin, C.D., Geller, A.M., Mailman, R.B., Drago, J., Lawler, C.P., Gallagher, M. (1998a) Behavioural assessment of mice lacking DIA dopamine receptors. Neuroscience. 86: 135–146.PubMedGoogle Scholar
  132. Smith, G.W., Aubry, J.M., Dellu, F., Contarino, A., Bilezikjian, L.M., Gold, L.H., Chen, R., Marchuk, Y., Hauser, C., Bentley, C.A., Sawchenko, P.E., Koob, G.F., Vale, W., Lee, K.F. (1998b) Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron. 20: 1093–1102.PubMedGoogle Scholar
  133. Sokoloff, P., Giros, B., Martres, M.P., Bouthenet, M.L., Schwartz, J.C. (1990) Molecular cloning and characterization of a novel dopamine receptor ( D3) as a target for neuroleptics. Nature. 347: 146–151.Google Scholar
  134. Sokoloff, P. and Schwartz, J.C. (1995) Novel dopamine receptors half a decade later. Trends Pharmacol Sci. 16: 270–275.PubMedGoogle Scholar
  135. Steiner, H., Fuchs, S., Accili, D. (1997) D3 dopamine receptor-deficient mouse: evidence for reduced anxiety. Physiol Behay. 63: 137–141.Google Scholar
  136. 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
  137. Sutton, R.E., Koob, G.F., Le Moal, M., Rivier, J., Vale, W. (1982) Corticotropin releasing factor produces behavioural activation in rats. Nature. 297: 331–333.PubMedGoogle Scholar
  138. Swerdlow, N.R., and Geyer, M.A. (1998) Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophrenia Bull. 24: 285–301.Google Scholar
  139. Tallman, J. F., Paul, S. M., Skolnick, P., Gallager, D. W. (1980) Receptors for the age of anxiety: Pharmacology of the benzodiazepines. Science 207: 274–281.PubMedGoogle Scholar
  140. Tecott, L.H., Logue, S.F., Wehner, J.M., Kauer, J.A. (1998) Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice. Proc Natl Acad Sci U S A. 95: 15026–15031.PubMedGoogle Scholar
  141. Timpl, P., Spanagel, R., Sillaber, I., Kresse, A., Reul, J.M., Stalla, G.K., Blanquet, V., Steckler, T., Holsboer, F., Wurst, W. (1998) Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor. Nat Genet. 19: 162–166.PubMedGoogle Scholar
  142. Treit, D. and Fundytus, M. (1988) Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol Biochem Behay. 3 1: 959–962.Google Scholar
  143. Treit, D., Pinel, J.P., Fibiger, H.C. (1981) Conditioned defensive burying: a new paradigm for the study of anxiolytic agents. Pharmacol Biochem Behay. 15: 619–626.Google Scholar
  144. Trullas, R. and Skolnick, P. (1993). Differences in fear motivated behaviors among inbred mouse strains. Psychopharmacology. 111: 323–331.PubMedGoogle Scholar
  145. Tyrer, P.J. (1990) The division of neurosis: a failed classification. J R Soc Med. 83: 614–616.PubMedGoogle Scholar
  146. Vogel, R.A., Frye, G.D., Wilson, J.H., Kuhn, C.M., Koepke, K.M., Mailman, R.B., Mueller, R.A., Breese, G.R. (1980) Attenuation of the effects of punishment by ethanol: comparisons with chlordiazepoxide. Psychopharmacology. 71: 123–129.PubMedGoogle Scholar
  147. Walker, D.L. and Davis, M. (1997) Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear. J Neurosci. 17: 9375–9383.PubMedGoogle Scholar
  148. Walther, T., Voigt, J.P., Fukamizu, A., Fink, H., Bader, M. (1999) Learning and anxiety in angiotensindeficient mice. Behav Brain Res. 100: 1–4.PubMedGoogle Scholar
  149. Weninger, S.C., Dunn, A.J., Muglia, L.J., Dikkes, P., Miczek, K.A., Swiergiel, A.H., Berridge, C.W., Majzoub, J.A. (1999) Stress-induced behaviors require the corticotropin-releasing hormone ( CRH) receptor, but not CRH. Proc Natl Acad Sci U S A. 96: 8283–8288.Google Scholar
  150. Wehner J.M. and Silva, A. (1996) Importance of strain differences in evaluations of learning and memory processes in null mutants. Ment Retard Devel Disabilities Res Rev. 2: 243–248.Google Scholar
  151. Weiner, I., Shadach, E., Tarrasch, R., Kidron, R., Feldon, J. (1996) The latent inhibition model of schizophrenia: Further validation using the atypical neuroleptic, clozapine. Biol Psychiat. 40: 834–843.Google Scholar
  152. Wood, G.K., Tomasiewicz, H., Rutishauser, U., Magnuson, T., Quirion, R., Rochford, J., Srivastava, L.K. (1998) NCAM-180 knockout mice display increased lateral ventricle size and reduced prepulse inhibition of startle. Neuro Report. 16: 461–466.Google Scholar
  153. Xu, M., Hu, X.T., Cooper, D.C., Moratalia, R., Graybiel, A.M., White, F.J., Tonegawa, S. (1994a) Elmination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in D1 receptor mutant mice. Cell. 79: 945–955.PubMedGoogle Scholar
  154. Xu, M., Koeltzow, T.E., Santiago, G.T., Moratalla, R., Cooper, D.C., Hu, X.T., White, N.M., Graybiel, A.M., White, F.J., Tonegawa, S. (1997) Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of Dl and D2 receptors. Neuron. 19: 837–848.PubMedGoogle Scholar
  155. Xu, M., Moratalia, R., Gold, L.H., Hiroi, N., Koob, G.F., Graybiel, A.M., Tonegawa, S. (1994b): Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell. 79: 729–742.PubMedGoogle Scholar
  156. Zhuang, X., Gross, C., Santarelli, L., Compan, V., Trillat, A.C., Hen, R. (1999) Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharmacology. 21: 52–60.Google Scholar

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© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Andrew Holmes
  • Jacqueline N. Crawley

There are no affiliations available

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