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Molecular pathways of anxiety revealed by knockout mice

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Abstract

Anxiety is a normal reaction to threatening situations, and serves a physiological protective function. Pathological anxiety is characterized by a bias to interpret ambiguous situations as threatening, by avoidance of situations that are perceived to be harmful, and/or by exaggerated reactions to threat. Although much evidence indicates the involvement of the γ-aminobutyric acid, serotonin, norepinephrine, dopamine, and neuropeptide transmitter systems in the pathophysiology of anxiety, little is known about how anxiety develops and what genetic/environmental factors underlie susceptibility to anxiety. Recently, inactivation of several genes, associated with either chemical communication between neurons or signaling within neurons, has been shown to give rise to anxiety-related behavior in knockout mice. Apart from confirming the involvement of serotonin, γ-aminobutyric acid, and corticotrophin-releasing hormone as major mediators of anxiety and stress related behaviors, two novel groups of anxiety-relevant molecules have been revealed. The first group consists of neurotrophic-type molecules, such as interferon γ, neural cell adhesion molecule, and midkine, which play important roles in neuronal development and cell-to-cell communication. The second group comprises regulators of intracellular signaling and gene expression, which emphasizes the importance of gene regulation in anxiety-related behaviors. Defects in these molecules are likely to contribute to the abnormal development and/or function of neuronal networks, which leads to the manifestation of anxiety disorders.

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Abbreviations

5-HT:

5-hydroxytryptamine

5HTR:

5HT receptor

A2aR:

adenosine 2a receptor

ApoE:

apolipoprotein E

CaMKII:

α-calcium/calmodulin-dependent protein kinase II

CCK:

cholecystokinin

COMT:

catechol-O-methyl transferase

CRE:

cAMP-responsive element

CREM:

CRE modulator protein

CRH:

corticotrophin-releasing hormone

CRHR:

corticotrophin-releasing hormone receptor

DA:

dopamine

EPM:

elevated plus maze

FMRP:

FragileX mental retardation protein

GABA:

γ-aminobutyric acid

GABAAR:

GABAA receptor

GAD:

glutamic acid decarboxylase

GR:

glucocorticoid receptor

HPA:

hypothalamic-pituitary-adrenal system

NCAM:

neural cell adhesion molecule

NE:

norepinephrine

nAChR:

nicotinic acetylcholine receptor

NPY:

neuropeptide Y

OFQ/N:

orphanin FQ/nociceptin

PKC:

protein kinase C

References

  1. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington, DC.

    Google Scholar 

  2. Noyes R. and Hoehn-Saric R. (1998) The Anxiety Disorders. Cambridge University Press, Cambridge, UK.

    Google Scholar 

  3. Weiss S. M., Lightowler S., Stanhope K. J., Kennett G. A. And Dourish C. T. (2000) Measurement of anxiety in transgenic mice. Rev. Neurosci. 11, 59–74.

    PubMed  CAS  Google Scholar 

  4. Crawley J. N. (1999) Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res. 835, 18–26.

    PubMed  CAS  Google Scholar 

  5. Rodgers R. J. (1997) Animal models of ‘anxiety’: where next? Behav. Pharmacol. 8, 477–496.

    PubMed  CAS  Google Scholar 

  6. Lister R. G. (1987) The use of a plus maze to measure anxiety in the mouse. Psychopharmacology 92, 180–185.

    PubMed  CAS  Google Scholar 

  7. Rodgers R. J. and Johnson N. J. T. (1995) Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol. Biochem. Behav. 52, 297–303.

    PubMed  CAS  Google Scholar 

  8. Treit D. and Fundytus M. (1988) Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol. Biochem. Behav. 31, 959–962.

    PubMed  CAS  Google Scholar 

  9. Crawley J. N. (1981) Neuropharmacological specificity for a simple animal model for the behavioural actions of benzodiazepines. Pharamcol. Biochem. Behav. 15, 695–699.

    CAS  Google Scholar 

  10. Davis M. (1990) Animal models of anxiety based on classical conditioning: the conditioned emotional response (CER) and the fear-potentiated startle effect. Pharmacol. Ther. 47, 147–165.

    PubMed  CAS  Google Scholar 

  11. File S. E. (1985) Animal models for predicting clinical efficacy of anxiolytic drugs: social behaviour. Neuropsychobiology 13, 55–62.

    PubMed  CAS  Google Scholar 

  12. Berrettini W. H., Harris N., Ferraro T. N., and Vogel W. H. (1994) Maudsley reactive and non-reactive rats differ in exploratory behavior but not in learning. Psychiatr. Genet. 4, 91–94.

    PubMed  CAS  Google Scholar 

  13. Mathis C., Neumann P. E., Gershenfeld H., Paul S. M., and Crawley J. N. (1995) Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains. Behav. Genet. 25, 557–568.

    PubMed  CAS  Google Scholar 

  14. Pratt J. A. (1992) The neuroanatomical basis of anxiety. Pharmacol. Ther. 55, 149–81.

    PubMed  CAS  Google Scholar 

  15. Sullivan G. M., Coplan J. D., Kent J. M., and Gorman J. M. (1999) The noradrenergic system in pathological anxiety: A focus on panic with relevance to generalized anxiety and phobias. Biol. Psych. 46, 1205–1218.

    CAS  Google Scholar 

  16. LeDoux J. E. (2000) Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184.

    PubMed  CAS  Google Scholar 

  17. Cahill L. and McGaugh J. L. (1998) Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci. 21, 294–299.

    PubMed  CAS  Google Scholar 

  18. Davis M., Rainnie D., and Cassell M. (1994) Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci. 17, 208–214.

    PubMed  CAS  Google Scholar 

  19. File S. E., Kenny P. J., and Cheeta S. (2000) The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety. Pharm. Biochem. Behav. 66, 65–72.

    CAS  Google Scholar 

  20. Schlegel S., Steinert H., Bockisch A., Hahn K., Schloesser R., and Benkert O. (1994) Decreased benzodiazepine receptor binding in panic disorder measured by IOMAZENIL-SPECT. A preliminary report. Eur. Arch. Psychiatry Clin. Neurosci. 244, 49–51.

    PubMed  CAS  Google Scholar 

  21. Kaschka W., Feistel H., and Ebert D. (1995) Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J. Psychiatr. Res. 29, 427–434.

    PubMed  CAS  Google Scholar 

  22. Tiihonen J., Kuikka J., Rasanen P., Lepola U., Koponen H., Liuska A., et al. (1997) Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol. Psychiatry 2, 463–471.

    PubMed  CAS  Google Scholar 

  23. Nutt D. J., Glue P., Lawson C., and Wilson S. (1990) Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch. Gen. Psychiatry 47, 917–925.

    PubMed  CAS  Google Scholar 

  24. Belzung C., Misslin R., Vogel E., Dodd R. H., and Chapouthier G. (1987) Anxiogenic effects of methyl-beta-carboline-3-carboxylate in a light/dark choice situation. Pharmacol. Biochem. Behav. 28, 29–33.

    PubMed  CAS  Google Scholar 

  25. Sanders S. K. and Shekhar A. (1995) Regulation of anxiety by GABAA receptors in the rat amygdala. Pharmacol. Biochem. Behav. 52, 701–706.

    PubMed  CAS  Google Scholar 

  26. Dalvi A. and Rodgers R. J. (1996) GABAergic influences on plus-maze behaviour in mice. Psychopharmacology 128, 380–397.

    Google Scholar 

  27. Smith S. S., Gong Q. H., Hsu F. C., Markowitz R. S., Ffrench-Mullen J. M., and Li X. (1998) GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392, 926–930.

    PubMed  CAS  Google Scholar 

  28. Essrich C., Lorez M., Benson J. A., Fritschy J. M., and Luscher B. (1998) Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat. Neurosci. 1, 563–571.

    PubMed  CAS  Google Scholar 

  29. Rudolph U., Crestani F., Benke D., Brunig I., Benson J. A., Fritschy J. M., et al. (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401, 796–800.

    PubMed  CAS  Google Scholar 

  30. McKernan R. M., Rosahl T. W., Reynolds D. S., Sur C., Wafford K. A., Atack J. R., et al. (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alphal subtype. Nat. Neurosci. 3, 587–592.

    PubMed  CAS  Google Scholar 

  31. Low K., Crestani F., Keist R., Benke D., Brunig I., Benson J. A., et al. (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134.

    PubMed  CAS  Google Scholar 

  32. Johnston A. L. and File S. E. (1986) 5-HT and anxiety: promises and pitfalls. Pharmacol Biochem. Behav. 24, 1467–1470.

    PubMed  CAS  Google Scholar 

  33. Barrett J. E. and Vanover K. E. (1993) 5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions. Psychopharmacology 112, 1–12.

    PubMed  CAS  Google Scholar 

  34. Bremner J. D., Krystal J. H., Southwick S. M., and Charney D. S. (1996a) Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse 23, 28–38.

    Google Scholar 

  35. Bremner J. D., Krystal J. H., Southwick S. M., and Charney D. S. (1996b) Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23, 39–51.

    Google Scholar 

  36. Griebel G. (1999) Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders? Pharmacol. Ther. 82, 1–61.

    PubMed  CAS  Google Scholar 

  37. Heilig M., and Widerlov E. (1990) Neuropeptide Y: an overview of central distribution, functional aspects, and possible involvement in neuropsychiatric illnesses. Acta Psychiatr. Scand. 82, 95–114.

    PubMed  CAS  Google Scholar 

  38. Heilig M., Soderpalm B., Engel J. A., and Widerlov E. (1989) Centrally administered neuropeptide Y (NPY) produces anxiolytic-like effects in animal anxiety models. Psychopharmacology 98, 524–529.

    PubMed  CAS  Google Scholar 

  39. Wahlestedt C., Pich E. M., Koob G. F., Yee F., and Heilig M. (1993) Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides. Science 259, 528–531.

    PubMed  CAS  Google Scholar 

  40. Sutton R. E., Koob G. F., Le Moal M., Rivier J., and Vale W. (1982) Corticotropin releasing factor produces behavioural activation in rats. Nature 297, 331–333.

    PubMed  CAS  Google Scholar 

  41. Sherman J. E. and Kalin N. H. (1987) The effects of ICV-CRH on novelty-induced behavior. Pharmacol. Biochem. Behav. 26, 699–703.

    PubMed  CAS  Google Scholar 

  42. Berridge C. W. and Dunn A. J. (1989) Restraint-stress-induced changes in exploratory behavior appear to be mediated by norepinephrine-stimulated release of CRF. J. Neurosci. 9, 3513–3521.

    PubMed  CAS  Google Scholar 

  43. Butler P. D., Weiss J. M., Stout J. C., and Nemeroff C. B. (1990) Corticotrophin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus. J. Neurosci. 10, 176–83.

    PubMed  CAS  Google Scholar 

  44. 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.

    PubMed  CAS  Google Scholar 

  45. Stenzel-Poore M. P., Heinrichs S. C., Rivest S., Koob G. F., and Vale W. W. (1994) Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J. Neurosci. 14, 2579–2584.

    PubMed  CAS  Google Scholar 

  46. Dauge V., and Lena I. (1998) CCK in anxiety and cognitive processes. Neurosci. Biobehav. Rev. 22, 815–825.

    PubMed  CAS  Google Scholar 

  47. Brodin E., Rosen A., Schott E., and Brodin K. (1994) Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, choleycystokinin and somatostatin levels in the periaqueductal grey and limbic regions. Neuropepstides 26, 253–260.

    CAS  Google Scholar 

  48. Otsuka M., and Yoshioka K. (1993) Neurotransmitter functions of mammalian tachykinins. Physiol. Rev. 73, 229–308.

    PubMed  CAS  Google Scholar 

  49. Nikolaus S., Huston J. P., and Hasenohrl R. U. (1999) The neurokinin-1 receptor antagonist WIN51,708 attenuates the anxiolytic-like effects of ventralpallidal substance P injection. Neuroreport 10, 2293–2296.

    PubMed  CAS  Google Scholar 

  50. File S. E. (2000) NKP608, an NK1 receptor antagonist, has an anxiolytic action in the social interaction test in rats. Psychopharmacology 152, 105–109.

    PubMed  CAS  Google Scholar 

  51. Rupniak N. M. J., Carlson E. C., Harrsion T., Oates B., Seward E., Owen S., et al. (2000) Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalization in guinea-pigs and mice. Neuropharmacology 39, 1413–1421.

    PubMed  CAS  Google Scholar 

  52. 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.

    PubMed  CAS  Google Scholar 

  53. Sherif F., Harro J., el-Hwuegi A., and Oreland L. (1994) Anxiolytic-like effect of the GABA-transaminase inhibitor vigabatrin (gammavinyl GABA) on rat exploratory activity. Pharmacol. Biochem. Behav. 49, 801–805.

    PubMed  CAS  Google Scholar 

  54. Gogos J. A., Morgan M., Luines V., Santha M., Ogawa S., Pfaff D., and Karayiorgou M. (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behaviour. Proc. Natl. Acad. Sci. USA 95, 9991–9996.

    PubMed  CAS  Google Scholar 

  55. Bannon A. W., Seda J., Carmouche M., Francis J. M., Norman M. H., Karbon B., and McCaleb M. L. (2000) Behavioural characterization of neuropeptide Y knockout mice. Brain Res. 868, 79–87.

    PubMed  CAS  Google Scholar 

  56. Inui A., Okita M., Nakajima M., Momose K., Ueno N., Teranishi A., et al. (1998) Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y. Proc. Assoc. Am. Physicians 110, 171–182.

    PubMed  CAS  Google Scholar 

  57. Illes P. and Regenold J. T. (1990) Interaction between neuropeptide Y and noradrenaline on central catecholamine neurons. Nature 344, 62–63.

    PubMed  CAS  Google Scholar 

  58. Kombian S. B. and Colmers W. F. (1992) Neuropeptide Y selectively inhibits slow synaptic potentials in rat dorsal raphe nucleus in vitro by a presynaptic action. J. Neurosci. 12, 1086–1093.

    PubMed  CAS  Google Scholar 

  59. Konig M., Zimmer A. M., Steiner H., Holmes P. V., Crawley J. N., Brownstein M. J., and Zimmer A. (1996) Pain responses, anxiety and aggression in mice deficient in preproenkephalin. Nature 383, 535–538.

    Google Scholar 

  60. Good A. J. and Westbrook R. F. (1995) Effects of a microinjection of morphine into the amygdala on the acquisition and expression of conditioned fear and hypoalgesia in rats. Behav. Neurosci. 109, 631–41.

    PubMed  CAS  Google Scholar 

  61. Kang W., Wilson S. P., and Wilson M. A. (2000) Overexpression of proenkephalin in the amygdala potentiates the anxiolytic effects of benzodiazepines. Neuropsychopharmacology 22, 77–88.

    PubMed  CAS  Google Scholar 

  62. Koster A., Montkowski A., Schulz S., Stube E. M., Knaudt K., Jenck F., et al. (1999) Targeted disruption of the orphanin FQ/nociceptin gene increases susceptibility and impairs stress adaptation in mice. Proc. Natl. Acad. Sci. USA 96, 10,444–10,449.

    CAS  Google Scholar 

  63. Kustova Y., Sei Y., Morse H. C., and Basile A. S. (1998) The influence of targeted deletion of the IFNγ gene on emotional behaviours. Brain Behav. Immun. 12, 308–324.

    PubMed  CAS  Google Scholar 

  64. Stork O., Welzl H., Wotjak C. T., Hoyer D., Delling M., Cremer H., and Schachner M. (1999) Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. J. Neurobiol. 40, 343–355.

    PubMed  CAS  Google Scholar 

  65. Zhang N. and Duel T. F. (1999) Pleiotrophin and midkine, a family of mitogenic and angiogenic heparin-binding growth and differentiation factors. Curr. Opin. Hem. 6, 44–50.

    CAS  Google Scholar 

  66. Nakamura E., Kodomatsu K., Yuasa S., Muramatsu H., Mamiya T., Nabeshima T., et al. (1998) Disruption of the midkine gene (Mdk) resulted in altered expression of a calcium binding protein in the hippocampus of infant mice and their abnormal behaviour. Genes Cells 3, 811–822.

    PubMed  CAS  Google Scholar 

  67. Raber J., Akana S. F., Bhatnagar S., Dallman M. F., Wong D., and Mucke L. (2000) Hypothalamic-pituitary-adrenal dysfunction in Apoe-/-mice: possible role in behavioural and metabolic alterations. J. Neurosci. 20, 2064–2071.

    PubMed  CAS  Google Scholar 

  68. Gutman C. R., Strittmatter W. J., Weisgraber K. H., and Matthew W. D. (1997) Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor. J. Neurosci. 17, 6114–6121.

    PubMed  CAS  Google Scholar 

  69. Sun Y., Wul S., Bu G., Onifade M. K., Patel S. N., LaDu M. J., Fagan A. M., and Holtzman D. M. (1998) Glial fibrillary acidic proteinapolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins. J. Neurosci. 18, 3261–3272.

    PubMed  CAS  Google Scholar 

  70. Crestani F., Lorez M., Baer K., Essrich C., Benke D., Laurent J. P., et al. (1999) Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat. Neurosci. 2, 833–839.

    PubMed  CAS  Google Scholar 

  71. Parks C. L., Robinson P. S., Sibille E., Shenk T., and Toth M. (1998) Increased anxiety of mice lacking the serotonin 1A receptor. Proc. Natl. Acad. Sci. USA 95, 10,734–10,739.

    CAS  Google Scholar 

  72. Heisler L. K., Chu H. M., Brennan T. J., Danao J. A., Bajwa P., Parsons L. H., and Tecott L. H. (1998) Elevated anxiety and antidepressantlike responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl. Acad. Sci. USA 95, 15,049–15,054.

    CAS  Google Scholar 

  73. Ramboz S., Oosting R., Ait amara D., Kung H. F., Blier P., Mendelsohn M., Mann J. J., Brunner D., and Hen R. (1998) Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc. Natl. Acad. Sci. USA 95, 14,476–14,481.

    CAS  Google Scholar 

  74. Zhuang X., Gross C., Ramboz S., Stark K., Beck S., and Hen R. (2000) Functional rescue of postsynaptic 5-HT1A receptors. Soc. Neurosci. Abstr. 121.

  75. Sibille E., Pavlides C., Benke D., and Toth M. (2000) Genetic inactivation of the serotonin (1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J. Neurosci. 20, 2758–2765.

    PubMed  CAS  Google Scholar 

  76. Boschert U., Ait Amara D., Segu L., and Hen R. (1994) The mouse 5-hydroxytryptamine 1B receptor is localized predominantly on axon terminals. Neuroscience 58, 167–182.

    PubMed  CAS  Google Scholar 

  77. Gothert M. (1990) Presynaptic serotonin receptors in the central nervous system. Ann. NY Acad. Sci. 604, 102–112.

    PubMed  CAS  Google Scholar 

  78. Saudou F., Ait Amara D., Dierich A., LeMeur M., Ramboz S., Segu L., Bulhot M. C., and Hen R. (1994) Enhanced aggressive behaviour in mice lacking 5-HT1B receptor. Science 265, 1875–1878.

    PubMed  CAS  Google Scholar 

  79. Ramboz S., Saudou F., Ait Amara D., Belzung C., Segu L., Misslin R., Buhot M. C., and Hen R. (1996) 5-HT1B receptor knockout — behavioural consequences. Behav. Brain Res. 73, 305–312.

    Google Scholar 

  80. Malleret G., Hen R., Guillou J. L., Segu L., and Bulhot M. C. (1999) 5-HT1B receptor knockout mice exhibit increased exploratory activity and enhanced spatial memory performance in the morris water maze. J. Neurosci. 19, 6157–6168.

    PubMed  CAS  Google Scholar 

  81. Brunner D., Buhot M. C., Hen R., and Hofer M. (1999) Anxiety, motor activation and maternal-infant interactions in 5-HT1B knockout mice. Behav. Neurosci. 113, 1–15.

    Google Scholar 

  82. Vaughan J., Donaldson C., Bittencourt J., Perrin M. H., Lewis K., Sutton S., et al. (1995) Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378, 287–292.

    PubMed  CAS  Google Scholar 

  83. Moreau J. L., Kilpatrick G., and Jenck F. (1997) Urocortin, a novel neuropeptide with anxiogenic-like properties. Neuroreport 8, 1697–1701.

    PubMed  CAS  Google Scholar 

  84. Timpl P., Spanagel R., Sillaber I., Kresse A., Reul J. M. H. M., Stalla G. K., et al. (1998) Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat. Genet. 19, 162–166.

    PubMed  CAS  Google Scholar 

  85. Smith G., Aubry J. M., Dellu F., Contarino A., Bilezikjian L. M., Gold L. H., et al. (1998) Corticotorpin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response and aberrant neuroendocrine development. Neuron 20, 1093–1102.

    PubMed  CAS  Google Scholar 

  86. Contarino A., Dellu F., Koob G. F., Smith G. W., Lee K. F., Vale W., and Gold L. H. (1999) Reduced anxiety-like behaviour and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Res. 835, 1–9.

    PubMed  CAS  Google Scholar 

  87. Bale T. L., Contarino A., Smith G. W., Chan R., Gold L. H., Sawchenko P. E., Koob G. F., Vale W., and 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.

    PubMed  CAS  Google Scholar 

  88. Kishimoto T., Radulovic J., Radulovi M., Lin C. R., Schrick C., Hooshmand F., et al. (2000) Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat. Genet. 24, 415–419.

    PubMed  CAS  Google Scholar 

  89. Coste S. C., Kesterson R. A., Heldwein K. A., Stevens S. L., Heard A. D., Hollis J. H., et al. (2000) Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat. Genet. 24, 403–409.

    PubMed  CAS  Google Scholar 

  90. Steiner H., Fuchs S., and Accili D. (1998) D3 dopamine receptor-deficient mouse: evidence for reduced anxiety. Physiol. Behav. 63, 137–141.

    Google Scholar 

  91. Dulawa S. C., Grandy D. K., Low M. J., Paulus M. P., and Geyer M. A. (1999) Dopamine D4 receptor knock-out mice exhibit reduced exploration of novel stimuli. J. Neurosci. 19, 9950–9556.

    Google Scholar 

  92. Walther T., Balschun D., Voigt J.-P., Fink H., Zuschratter W., Birchmeier C., Ganten D., and Bader M. (1998) Sustained long term potentiation and anxiety in mice lacking the Mas protooncogene. J. Biol. Chem. 273, 11,867–11,873.

    CAS  Google Scholar 

  93. Wilson W., Voigt P., Bader M., Marsden C. A., and Fink H. Behaviour of the transgenic (mREN2)27 rat. Brain Res. 729, 1–9.

  94. Walther T., Voigt J. P., Fukamizu A., Fink H., and Bader M. (1999) Learning and anxiety in angiotensin-deficient mice. Behav. Brain Res. 100, 1–4.

    PubMed  CAS  Google Scholar 

  95. Ledent C., Vaugeois J. M., Schiffmann S. N., Pderazzini T., El Yacoubi M., Vanderhaeghen J. J., et al. (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388, 674–678.

    PubMed  CAS  Google Scholar 

  96. Baldwin H. A. and File S. E. (1989) Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors. Pharmacol. Biochem. Behav. 32, 181–186.

    PubMed  CAS  Google Scholar 

  97. Schiffmann S. N. and Vanderhaeghen J. J. (1993) Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J. Neurosci. 13, 1080–1087.

    PubMed  CAS  Google Scholar 

  98. Paylor R., Nguyen M., Crawley J. N., Patrick J., Beaudet A., and Orr-Urtreger A. (1998) Alpha-7 nicotinic receptor subunits are not necessary for hippocampal-dependent learning or sensorimotor gating — a behavioural characterization of ACR7-deficient mice. Learn. Mem. 5, 302–316.

    PubMed  CAS  Google Scholar 

  99. Ross S. A., Wong J. Y., Clifford J. J., Kinsella A., Massalas J. S., Horne M. K., et al. (2000) Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knockout mouse. J. Neurosci. 20, 6431–6441.

    PubMed  CAS  Google Scholar 

  100. Costall B., Kelly M. E., Naylor R. J., and Onaivi E. S. (1989) The actions of nicotine and cocaine in a mouse model of anxiety. Pharmacol. Biochem. Behav. 33, 197–203.

    PubMed  CAS  Google Scholar 

  101. Brioni J. D., O’Neill A. B., Kim D. J., and Decker M. W. (1993) Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test. Eur. J. Pharmacol. 238, 1–8.

    PubMed  CAS  Google Scholar 

  102. Muglia L. M., Schaefer M. L., Vogt S. K., Gurtner G., Imamura A., and Muglia L. J. (1999) The 5′-flanking region of the mouse adenylyl cyclase type VIII gene imparts tissue-specific expression in transgenic mice. J. Neurosci. 19, 2051–2058.

    PubMed  CAS  Google Scholar 

  103. Schaefer M. L., Wong S. T., Wozniak D. F., Muglia L. M., Liauw J. A., Zhuo M., et al. (2000) Altered stress-induced anxiety in adenylyl cyclase type VIII deficient mice. J. Neurosci. 20, 4809–4820.

    PubMed  CAS  Google Scholar 

  104. Sassone-Corsi P. (1995) Transcription factors responsive to cAMP. Annu. Rev. Cell Dev. Biol. 11, 355–377.

    PubMed  CAS  Google Scholar 

  105. Maldonado R., Smadja C., Mazucchelli C., and Sassone-Corsi P. (1999) Altered emotional and locomotor responses in mice deficient in the transcription factor CREM. Proc. Natl. Acad. Sci. USA 96, 14094–14099.

    PubMed  CAS  Google Scholar 

  106. 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.

    PubMed  CAS  Google Scholar 

  107. Kennedy M. B. (1997) The postsynaptic density at glutamatergic synapses. Trends Neurosci. 20, 264–268.

    PubMed  CAS  Google Scholar 

  108. Braun A. P. and Schulman H. (1995) The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. Annu. Rev. Neurosci. 57, 417–445.

    CAS  Google Scholar 

  109. Bowers B. J., Collins A. C., Tritto T., and Wehner J. M. (2000) Mice lacking PKCγ exhibit decreased anxiety. Behav. Genet. 30, 111–121.

    PubMed  CAS  Google Scholar 

  110. Wafford K. A., Burnett D. M., Leidenheimer N. J., Burt D. R., Wang J. B., Kofuji P., et al. (1991) Ethanol sensitivity of the GABAA receptor expressed in xenopus oocytes requires 8 amino acids contained in the g2L subunit. Neuron 7, 27–33.

    PubMed  CAS  Google Scholar 

  111. Harris R. A., McQuilkwn S. J., Paylor R., Abeliovich A., Tonegawa A., and Wehner J. M. (1995) Mutant mice lacking the γ-isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of γ-aminobutyrate type A receptors. Proc. Natl. Acad. Sci. USA 92, 3658–3662.

    PubMed  CAS  Google Scholar 

  112. Miyakawa T., Yagi T., Watanabe S., and Niki H. (1994) Increased fearfulness of fyn tyrosine kinase deficient mice. Mol. Brain Res. 27, 179–182.

    PubMed  CAS  Google Scholar 

  113. Grant S. G. (1996) Analysis of NMDA receptor mediated synaptic plasticity using gene targeting: roles of Fyn and FAK non-receptor tyrosine kinases. J. Physiol. (Paris) 90, 337–338.

    Google Scholar 

  114. Beggs H. E., Baragona S. C., Hemperly J. J., and Maness P. F. (1997) NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn). J. Biol. Chem. 272, 8310–8319.

    PubMed  CAS  Google Scholar 

  115. Seiwa C., Sugiyama I., Yagi T., Iguchi T., and Asou H. (2000) Fyn tyrosine kinase participates in the compact myelin sheath formation in the central nervous system. Neurosci. Res. 37, 21–31.

    PubMed  CAS  Google Scholar 

  116. Vaillend C. and Ungerer A. (1999) Behavioural characterization of mdx3cv mice deficient in C-terminal dystrophins. Neuromusc. Disord. 9, 296–304.

    PubMed  CAS  Google Scholar 

  117. Blake D. J. and Kroger S. (2000) The neurobiology of Duchenne muscular dystrophy: learning lessons from muscle? Trends Neurosci. 23, 92–99.

    PubMed  CAS  Google Scholar 

  118. Reichardt H. M. and Schutz G. (1998) Glucocorticoid signaling — multiple variations of a common theme. Mol. Cell Endocrinol. 146, 1–6.

    PubMed  CAS  Google Scholar 

  119. Tronche F., Kellendonk C., Kretz O., Gass P., Anlag K., Orban P. C., Bock R., Klein R., and Schutz G. (1999) Disruption of glucocoricoid receptor gene in the nervous system results in reduced anxiety. Nat. Gen. 23, 99–103.

    CAS  Google Scholar 

  120. Peier A. M., McIlwain K. L., Kenneson A., Warren S. T., Paylor R., and Nelson D. L. (2000) (Over)correction of FMR1 deficiency with YAC transgenics: behavioural and physical features. Hum. Mol. Genet. 9, 1145–1159.

    PubMed  CAS  Google Scholar 

  121. Jin P. and Warren S. T. (2000) Understanding the molecular basis of fragile X syndrome. Hum. Mol. Genet. 9, 901–908.

    PubMed  CAS  Google Scholar 

  122. Comery T. A., Harris J. B., Willems P. J., Oostra B. A., Irwin S. A., Weiler I. J., and Greenough W. T. (1997) Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc. Natl. Acad. Sci. USA 94, 5401–5404.

    PubMed  CAS  Google Scholar 

  123. Weiler I. J., Irwin S. A., Klintsova A. Y., Spencer C. M., Brazelton A. D., Miyashiro K., et al. (1997) Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc. Natl. Acad. Sci. USA 94, 5395–5400.

    PubMed  CAS  Google Scholar 

  124. Chaouloff F. (1993) Physiopharmacological interactions between stress hormones and central serotonergic systems. Brain. Res. Rev. 18, 1–32.

    PubMed  CAS  Google Scholar 

  125. Chalmers D. T., Kwak S. P., Mansour A., Akil H., and Watson S. J. (1993) Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression. J. Neurosci. 13, 914–923.

    PubMed  CAS  Google Scholar 

  126. Semont A., Fache M., Ouafik L., Hery M., Faudon M., and Hery F. (1999) Effect of serotonin in hibition on glucocorticoid and mineralocorticoid expression in various brain structures. Neuroendocrinology 69, 121–128.

    PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Ave, 10021, New York, NY

    Sarah J. Wood & Miklos Toth

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Wood, S.J., Toth, M. Molecular pathways of anxiety revealed by knockout mice. Mol Neurobiol 23, 101–119 (2001). https://doi.org/10.1385/MN:23:2-3:101

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