Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

50 years of hurdles and hope in anxiolytic drug discovery

Key Points

  • Anxiety disorders are frequently diagnosed chronic, disabling conditions that impose enormous societal costs.

  • The main anxiety syndromes include panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobias, obsessive-compulsive disorder and post-traumatic stress disorder.

  • Treatment options, which include drugs acting on the GABA (γ-aminobutyric acid)–benzodiazepine and 5-hydroxytryptamine (5-HT; also known as serotonin) systems are available for most of these disorders. However, these compounds have limited efficacy and/or tolerability.

  • The urgent need for new, alternative treatments for anxiety has generated a vast amount of preclinical data and led to many drugs being taken though the laboratory to the clinic.

  • The clinical outcome of this huge effort has been disappointing, however, with laboratory rodent studies predicting very few promising new therapeutic leads.

  • This Review analyses the major trends from the preclinical data accrued over the past 50 years and highlights the most intensively investigated neurotransmitter systems: the GABA–benzodiazepine, serotonin, neuropeptide, glutamate and endocannabinoid systems.

  • We identify a number of key issues that may have hampered progress in the field.

  • Oft-cited explanations for the poor translational track record of preclinical anxiety studies include the lack of validity of the available rodent tests, the use of non-disease-susceptible animals, insufficient knowledge of the neurobiological anxiety systems and too much focus by pharmaceutical companies on single targets to find new anxiolytics.

  • Here, we offer recommendations for how anxiolytic drug discovery can be more effective going forward.

Abstract

Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)–benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Fifty-year trends in preclinical anxiolytic drug discovery.
Figure 2: The ten most commonly used tests in anxiolytic drug discovery.
Figure 3: Anxiety-related effects of drugs targeting the 5-HT, neuropeptide, glutamate and endocannabinoid systems.
Figure 4: Experiments in animal models that investigated the effects of drugs modulating neuropeptide systems in models of anxiety disorders from 1960 to 2012.
Figure 5: Fifty-year trends in the species, strain, sex and chronicity of drug treatment in anxiolytic drug discovery studies.
Figure 6: Recommendations for improving anxiolytic drug discovery.

References

  1. 1

    Kessler, R. C. The global burden of anxiety and mood disorders: putting the European Study of the Epidemiology of Mental Disorders (ESEMeD) findings into perspective. J. Clin. Psychiatry 68 (Suppl. 2), 10–19 (2007).

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Wittchen, H. U. et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur. Neuropsychopharmacol. 21, 655–679 (2011). This is a major landmark study that sheds new light on the state of Europe's mental and neurological health.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Kessler, R. C. et al. Development of lifetime comorbidity in the World Health Organization world mental health surveys. Arch. Gen. Psychiatry 68, 90–100 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Kessler, R. C. et al. The WHO World Mental Health (WMH) Surveys. Psychiatrie 6, 5–9 (2009).

    Google Scholar 

  5. 5

    Ormel, J. et al. Disability and treatment of specific mental and physical disorders across the world. Br. J. Psychiatry 192, 368–375 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Kupfer, D. J. & Regier, D. A. Neuroscience, clinical evidence, and the future of psychiatric classification in DSM-5. Am. J. Psychiatry 168, 672–674 (2011).

    Article  Google Scholar 

  7. 7

    Craddock, N. & Owen, M. J. The Kraepelinian dichotomy — going, going... but still not gone. Br. J. Psychiatry 196, 92–95 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Leucht, S., Heres, S. & Davis, J. M. Considerations about the efficacy of psychopharmacological drugs. Nervenartz 82, 1425–1430 (2011).

    Article  CAS  Google Scholar 

  9. 9

    Caspi, A., Hariri, A. R., Holmes, A., Uher, R. & Moffitt, T. E. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am. J. Psychiatry 167, 509–527 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Owen, D. R., Rupprecht, R. & Nutt, D. J. Stratified medicine in psychiatry: a worrying example or new opportunity in the treatment of anxiety? J. Psychopharmacol. 27, 119–122 (2013).

    Article  Google Scholar 

  11. 11

    Nothdurfter, C., Rupprecht, R. & Rammes, G. Recent developments in potential anxiolytic agents targeting GABAA/BzR complex or the translocator protein (18kDa) (TSPO). Curr. Top. Med. Chem. 12, 360–370 (2012).

    Article  CAS  Google Scholar 

  12. 12

    Belzung, C. & Lemoine, M. Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression. Biol. Mood Anxiety Disord. 1, 9–14 (2011). This paper refines the concepts of criteria of the validity of anxiety models based on recent developments.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Haller, J., Aliczki, M. & Gyimesine, P. K. Classical and novel approaches to the preclinical testing of anxiolytics: a critical evaluation. Neurosci. Biobehav. Rev. http://dx.doi.org/10.1016/j.neubiorev.2012.09.001 (2012).

  14. 14

    Cryan, J. F. & Holmes, A. The ascent of mouse: advances in modelling human depression and anxiety. Nature Rev. Drug Discov. 4, 775–790 (2005).

    Article  CAS  Google Scholar 

  15. 15

    McKinney, W. T. Jr & Bunney, W. E. Jr. Animal model of depression. I. Review of evidence: implications for research. Arch. Gen. Psychiatry 21, 240–248 (1969).

    Article  Google Scholar 

  16. 16

    Hall, C. S. Emotional behavior in the rat. I: defecation and urination as measures of individual differences in emotionality. J. Comp. Psychol. 18, 385–403 (1934).

    Article  Google Scholar 

  17. 17

    Handley, S. L. & Mithani, S. Effects of α-adrenoceptor agonists and antagonists in a maze-exploration model of 'fear'-motivated behaviour. Naunyn Schmiedeberg Arch. Pharmacol. 327, 1–5 (1984).

    Article  CAS  Google Scholar 

  18. 18

    Crawley, J. N. Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines. Pharmacol. Biochem. Behav. 15, 695–699 (1981).

    Article  CAS  Google Scholar 

  19. 19

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

    CAS  PubMed  Google Scholar 

  20. 20

    Vogel, J. R., Beer, B. & Clody, D. E. A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21, 1–7 (1971).

    Article  CAS  Google Scholar 

  21. 21

    Geller, I., Kulak, J. T. & Seifter, J. The effects of chlordiazepoxide and chlorpromazine on a punishment discrimination. Psychopharmacologia 3, 374–385 (1962).

    Article  CAS  Google Scholar 

  22. 22

    Griebel, G. & Beeské, S. in Mood and Anxiety Related Phenotypes in Mice (ed. Gould, T. D.) 97–106 (Springer, 2011).

    Book  Google Scholar 

  23. 23

    Blanchard, D. C., Griebel, G. & Blanchard, R. J. The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic. Eur. J. Pharmacol. 463, 97–116 (2003).

    Article  CAS  Google Scholar 

  24. 24

    Rodgers, R. J., Cao, B. J., Dalvi, A. & Holmes, A. Animal models of anxiety: an ethological perspective. Braz. J. Med. Biol. Res. 30, 289–304 (1997).

    Article  CAS  Google Scholar 

  25. 25

    Steckler, T. & Risbrough, V. Pharmacological treatment of PTSD — established and new approaches. Neuropharmacology 62, 617–627 (2012).

    Article  CAS  Google Scholar 

  26. 26

    Mozhui, K. et al. Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. J. Neurosci. 30, 5357–5367 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Belzung, C., El Hage, W., Moindrot, N. & Griebel, G. Behavioral and neurochemical changes following predatory stress in mice. Neuropharmacology 41, 400–408 (2001).

    Article  CAS  Google Scholar 

  28. 28

    Muigg, P. et al. Differential stress-induced neuronal activation patterns in mouse lines selectively bred for high, normal or low anxiety. PLoS ONE 4, e5346 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Holmes, A. & Singewald, N. Individual differences in recovery from traumatic fear. Trends Neurosci. 36, 23–31 (2013).

    Article  CAS  Google Scholar 

  30. 30

    Holmes, A. Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease. Neurosci. Biobehav. Rev. 32, 1293–1314 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Holmes, A. J. et al. Individual differences in amygdala-medial prefrontal anatomy link negative affect, impaired social functioning, and polygenic depression risk. J. Neurosci. 32, 18087–18100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Donaldson, Z. R., Nautiyal, K. M., Ahmari, S. E. & Hen, R. Genetic approaches for understanding the role of serotonin receptors in mood and behavior. Curr. Opin. Neurobiol. 23, 399–406 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Holmes, A. Targeted gene mutation approaches to the study of anxiety-like behavior in mice. Neurosci. Biobehav. Rev. 25, 261–273 (2001).

    Article  CAS  Google Scholar 

  34. 34

    Tye, K. M. & Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nature Rev. Neurosci. 13, 251–266 (2012).

    Article  CAS  Google Scholar 

  35. 35

    Tye, K. M. et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471, 358–362 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Johansen, J. P. et al. Optical activation of lateral amygdala pyramidal cells instructs associative fear learning. Proc. Natl Acad. Sci. USA 107, 12692–12697 (2010).

    Article  Google Scholar 

  37. 37

    Fisher, P. M. & Hariri, A. R. Linking variability in brain chemistry and circuit function through multimodal human neuroimaging. Genes Brain Behav. 11, 633–642 (2012).

    Article  CAS  Google Scholar 

  38. 38

    Holmes, A. & Quirk, G. J. Pharmacological facilitation of fear extinction and the search for adjunct treatments for anxiety disorders — the case of yohimbine. Trends Pharmacol. Sci. 31, 2–7 (2010).

    Article  CAS  Google Scholar 

  39. 39

    Myers, K. M. & Davis, M. Mechanisms of fear extinction. Mol. Psychiatry 12, 120–150 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Richardson, R., Ledgerwood, L. & Cranney, J. Facilitation of fear extinction by d-cycloserine: theoretical and clinical implications. Learn. Mem. 11, 510–516 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Baldwin, D. S. & Garner, M. in Handbook of Anxiety and Fear (eds Blanchard, R. J., Blanchard, D. C., Griebel, G. & Nutt, D.) 395–411 (Elsevier, 2008).

    Book  Google Scholar 

  42. 42

    Baldwin, D. S., Ajel, K. I. & Garner, M. Pharmacological treatment of generalized anxiety disorder. Curr. Top. Behav. Neurosci. 2, 453–467 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Hoffman, E. J. & Mathew, S. J. Anxiety disorders: a comprehensive review of pharmacotherapies. Mt. Sinai J. Med. 75, 248–262 (2008). This article reviews the evidence from randomized, placebo-controlled trials and meta-analyses of pharmacological treatments of the main anxiety disorders.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Rudolph, U. & Knoflach, F. Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nature Rev. Drug Discov. 10, 685–697 (2011).

    Article  CAS  Google Scholar 

  45. 45

    VanSteveninck, A. L. et al. Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol. Br. J. Clin. Pharmacol. 41, 565–573 (1996).

    Article  CAS  Google Scholar 

  46. 46

    Guldner, J. et al. Bretazenil modulates sleep EEG and nocturnal hormone secretion in normal men. Psychopharmacology 122, 115–121 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    de Haas, S. L. et al. The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A α2,3 selective agonist, in comparison with lorazepam in healthy volunteers. J. Psychopharmacol. 23, 625–632 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Surhone, L. M., Timpledon, M. T. & Marseken, S. F. Ocinaplon (VDM Publishing House, 2010).

    Google Scholar 

  49. 49

    de Haas, S. L. et al. Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J. Psychopharmacol. 21, 374–383 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Rupprecht, R. et al. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 325, 490–493 (2009).

    Article  CAS  Google Scholar 

  51. 51

    Owen, D. R. et al. Variation in binding affinity of the novel anxiolytic XBD173 for the 18 kDa translocator protein in human brain. Synapse 65, 257–259 (2011).

    Article  CAS  Google Scholar 

  52. 52

    Griebel, G. 5-hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research. Pharmacol. Ther. 65, 319–395 (1995).

    Article  CAS  Google Scholar 

  53. 53

    Lesch, K. P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531 (1996).

    Article  CAS  Google Scholar 

  54. 54

    Hariri, A. R. & Holmes, A. Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn. Sci. 10, 182–191 (2006).

    Article  Google Scholar 

  55. 55

    Belzung, C. & Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res. 125, 141–149 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Jacobson, L. H. & Cryan, J. F. Genetic approaches to modeling anxiety in animals. Curr. Top. Behav. Neurosci. 2, 161–201 (2010). This is a comprehensive review on models of anxiety involving targeted manipulation of candidate genes.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Goldberg, H. L. & Finnerty, R. J. The comparative efficacy of buspirone and diazepam in the treatment of anxiety. Am. J. Psychiatry 136, 1184–1187 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Rickels, K. et al. Buspirone and diazepam in anxiety: a controlled study. J. Clin. Psychiatry 43, 81–86 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Akimova, E., Lanzenberger, R. & Kasper, S. The serotonin-1A receptor in anxiety disorders. Biol. Psychiatry 66, 627–635 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Goodfellow, N. M., Benekareddy, M., Vaidya, V. A. & Lambe, E. K. Layer II/III of the prefrontal cortex: Inhibition by the serotonin 5-HT1A receptor in development and stress. J. Neurosci. 29, 10094–10103 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Zhang, J. et al. Neuronal nitric oxide synthase alteration accounts for the role of 5-HT1A receptor in modulating anxiety-related behaviors. J. Neurosci. 30, 2433–2441 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Chessick, C. A. et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst. Rev. 2006, CD006115 (2006).

    Google Scholar 

  63. 63

    Gammans, R. E., Mayol, R. F. & LaBudde, J. A. Metabolism and disposition of buspirone. Am. J. Med. 80, 41–51 (1986).

    Article  CAS  Google Scholar 

  64. 64

    Nutt, D. J. & Ballenger, J. C. Anxiety Disorders (Blackwell Science, 2003).

    Google Scholar 

  65. 65

    Kent, J. M., Coplan, J. D. & Gorman, J. M. Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety. Biol. Psychiatry 44, 812–824 (1998).

    Article  CAS  Google Scholar 

  66. 66

    Nutt, D. J. Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectr. 10, 49–56 (2005).

    Article  Google Scholar 

  67. 67

    Gartside, S. E., Umbers, V., Hajos, M. & Sharp, T. Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT. Br. J. Pharmacol. 115, 1064–1070 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Vaswani, M., Linda, F. K. & Ramesh, S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 85–102 (2003).

    Article  CAS  Google Scholar 

  69. 69

    Crabbe, J. C., Wahlsten, D. & Dudek, B. C. Genetics of mouse behavior: interactions with laboratory environment. Science 284, 1670–1672 (1999). This study demonstrates that almost undetectable environmental differences may have large behavioural consequences when using anxiety tests.

    Article  CAS  Google Scholar 

  70. 70

    Handley, S. L. & McBlane, J. W. An assessment of the elevated X-maze for studying anxiety and anxiety-modulating drugs. J. Pharmacol. Toxicol. Methods 29, 129–138 (1993).

    Article  CAS  Google Scholar 

  71. 71

    Sanger, D. J. Effects of buspirone and related compounds on suppressed operant responding in rats. J. Pharmacol. Exp. Ther. 254, 420–426 (1990).

    CAS  PubMed  Google Scholar 

  72. 72

    Maier, S. F. & Watkins, L. R. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci. Biobehav. Rev. 29, 829–841 (2005).

    Article  CAS  Google Scholar 

  73. 73

    Stein, D. J., Ahokas, A. A., & de Bodinat, C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 28, 561–566 (2008).

    Article  CAS  Google Scholar 

  74. 74

    Belzung, C., Yalcin, I., Griebel, G., Surget, A. & Leman, S. Neuropeptides in psychiatric diseases: an overview with a particular focus on depression and anxiety disorders. CNS Neurol. Disord. Drug Targets 5, 135–145 (2006).

    Article  CAS  Google Scholar 

  75. 75

    Holmes, A., Heilig, M., Rupniak, N. M., Steckler, T. & Griebel, G. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol. Sci. 24, 580–588 (2003).

    Article  CAS  Google Scholar 

  76. 76

    van den Pol, A. N. Neuropeptide transmission in brain circuits. Neuron 76, 98–115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Steckler, T. Developing small molecule nonpeptidergic drugs for the treatment of anxiety disorders: is the challenge still ahead? Curr. Top. Behav. Neurosci. 2, 415–428 (2010).

    Article  Google Scholar 

  78. 78

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

    Article  CAS  Google Scholar 

  79. 79

    Van der Haegen, J. J., Signeau, J. C. & Gepts, W. New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nature 257, 604–605 (1975).

    Article  Google Scholar 

  80. 80

    Moran, T. H., Robinson, P. H., Goldrich, M. S. & McHugh, P. R. Two brain cholecystokinin receptors: implications for behavioral actions. Brain Res. 362, 175–179 (1986).

    Article  CAS  Google Scholar 

  81. 81

    Griebel, G. & Holsboer, F. Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning? Nature Rev. Drug Discov. 11, 462–478 (2012).

    Article  CAS  Google Scholar 

  82. 82

    Vale, W. W., Spiess, J., Rivier, C. & Rivier, J. Characterization of a 41 residue ovine hypothalamic peptide that stimulates the secretion of corticotropin and β-endorphin. Science 213, 1394–1397 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Chalmers, D. T., Lovenberg, T. W. & De Souza, E. B. Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J. Neurosci. 15, 6340–6350 (1995).

    Article  CAS  Google Scholar 

  84. 84

    Turiault, M., Cohen, C. & Griebel, G. in Encyclopedia of Psychopharmacology (ed. Stolerman, I. P.) 1301–1303 (Springer-Verlag, 2010).

    Book  Google Scholar 

  85. 85

    Regoli, D., Boudon, A. & Fauchere, J. L. Receptors and antagonists for substance P and related peptides. Pharmacol. Rev. 46, 551–599 (1994).

    CAS  PubMed  Google Scholar 

  86. 86

    Griebel, G. & Beeske, S. Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases? Pharmacol. Ther. 133, 116–123 (2012).

    Article  CAS  Google Scholar 

  87. 87

    Brothers, S. P. & Wahlestedt, C. Therapeutic potential of neuropeptide Y (NPY) receptor ligands. EMBO Mol. Med. 2, 429–439 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Civelli, O. The orphanin FQ/nociceptin (OFQ/N) system. Results Probl. Cell Differ. 46, 1–25 (2008).

    Article  CAS  Google Scholar 

  89. 89

    Lang, R., Gundlach, A. L. & Kofler, B. The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol. Ther. 115, 177–207 (2007).

    Article  CAS  Google Scholar 

  90. 90

    Shimazaki, T., Yoshimizu, T. & Chaki, S. Melanin-concentrating hormone MCH1 receptor antagonists: a potential new approach to the treatment of depression and anxiety disorders. CNS Drugs 20, 801–811 (2006).

    Article  CAS  Google Scholar 

  91. 91

    Chung, S. et al. The melanin-concentrating hormone (MCH) system modulates behaviors associated with psychiatric disorders. PLoS ONE 6, e19286 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Xu, Y. L. et al. Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43, 487–497 (2004).

    Article  CAS  Google Scholar 

  93. 93

    Sah, R. & Geracioti, T. D. Neuropeptide Y and posttraumatic stress disorder. Mol. Psychiatry 18, 646–655 (2013).

    Article  CAS  Google Scholar 

  94. 94

    Krystal, J. H. et al. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 24, 669–693 (2010).

    Article  CAS  Google Scholar 

  95. 95

    Dunayevich, E. et al. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 33, 1603–1610 (2008).

    Article  CAS  Google Scholar 

  96. 96

    Bergink, V. & Westenberg, H. G. Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740. Int. Clin. Psychopharmacol. 20, 291–293 (2005).

    Article  Google Scholar 

  97. 97

    Sanacora, G., Zarate, C. A., Krystal, J. H. & Manji, H. K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Rev. Drug Discov. 7, 426–437 (2008).

    Article  CAS  Google Scholar 

  98. 98

    Ressler, K. J. et al. Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry 61, 1136–1144 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Norberg, M. M., Krystal, J. H. & Tolin, D. F. A meta-analysis of d-cycloserine and the facilitation of fear extinction and exposure therapy. Biol. Psychiatry 63, 1118–1126 (2008).

    Article  CAS  Google Scholar 

  100. 100

    Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990).

    Article  CAS  Google Scholar 

  101. 101

    Gunduz-Cinar, O. et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol. Psychiatry 18, 813–823 (2013).

    Article  CAS  Google Scholar 

  102. 102

    Neumeister, A. et al. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2013.61 (2013).

  103. 103

    Griebel, G., Stemmelin, J. & Scatton, B. Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol. Psychiatry 57, 261–267 (2005).

    Article  CAS  Google Scholar 

  104. 104

    Jacob, W. et al. Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: role of glutamatergic transmission. Genes Brain Behav. 8, 685–698 (2009).

    Article  CAS  Google Scholar 

  105. 105

    Haller, J., Varga, B., Ledent, C. & Freund, T. F. CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav. Pharmacol. 15, 299–304 (2004).

    Article  CAS  Google Scholar 

  106. 106

    Moreira, F. A. & Wotjak, C. T. Cannabinoids and anxiety. Curr. Top. Behav. Neurosci. 2, 429–450 (2010).

    Article  Google Scholar 

  107. 107

    Metna-Laurent, M. et al. Bimodal control of fear-coping strategies by CB1 cannabinoid receptors. J. Neurosci. 32, 7109–7118 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Topol, E. J. et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 376, 517–523 (2010).

    Article  CAS  Google Scholar 

  109. 109

    Hill, M. N. et al. Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol. Psychiatry http://dx.doi.org/10.1038/mp.2012.90 (2012).

  110. 110

    Bortolato, M. & Piomelli, D. in Handbook of Anxiety and Fear (eds Blanchard, R. J., Blanchard, D. C., Griebel, G. & Nutt, D.) 303–324 (Elsevier, 2008).

    Book  Google Scholar 

  111. 111

    Micale, V. et al. Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol. Ther. 138, 18–37 (2013).

    Article  CAS  Google Scholar 

  112. 112

    Collins, P. Y. et al. Grand challenges in global mental health. Nature 475, 27–30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

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

    Article  CAS  Google Scholar 

  114. 114

    Crestani, F., Martin, J. R., Mohler, H. & Rudolph, U. Resolving differences in GABAA receptor mutant mouse studies. Nature Neurosci. 3, 1059 (2000).

    Article  CAS  Google Scholar 

  115. 115

    Kessler, R. C. et al. Severity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Arch. Gen. Psychiatry 69, 381–389 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Blanchard, D. C., Griebel, G. & Blanchard, R. J. Gender bias in the preclinical psychopharmacology of anxiety: male models for (predominantly) female disorders. J. Psychopharmacol. 9, 79–82 (1995).

    Article  CAS  Google Scholar 

  117. 117

    Palanza, P. Animal models of anxiety and depression: how are females different? Neurosci. Biobehav. Rev. 25, 219–233 (2001).

    Article  CAS  Google Scholar 

  118. 118

    Soldin, O. P. & Mattison, D. R. Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet. 48, 143–157 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Hopkins, A. L. Network pharmacology: the next paradigm in drug discovery. Nature Chem. Biol. 4, 682–690 (2008).

    Article  CAS  Google Scholar 

  120. 120

    Youdim, M. B. & Buccafusco, J. J. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci. 26, 27–35 (2005).

    Article  CAS  Google Scholar 

  121. 121

    Besnard, J. et al. Automated design of ligands to polypharmacological profiles. Nature 492, 215–220 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Bottegoni, G., Favia, A. D., Recanatini, M. & Cavalli, A. The role of fragment-based and computational methods in polypharmacology. Drug Discov. Today 17, 23–34 (2012).

    Article  CAS  Google Scholar 

  123. 123

    Yizhar, O., Fenno, L. E., Davidson, T. J., Mogri, M. & Deisseroth, K. Optogenetics in neural systems. Neuron 71, 9–34 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Covington, H. E. et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J. Neurosci. 30, 16082–16090 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    American Psychiatric Association Taskforce on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR (American Psychiatric Association, 2000).

  126. 126

    Nutt, D. J., Garcia de Miguel, B. & Davies, S. J. C. in Handbook of Anxiety and Fear (eds Blanchard, R. J., Blanchard, D. C., Griebel, G. & Nutt, D. J.) 365–393 (Academic Press, 2008).

    Book  Google Scholar 

  127. 127

    Reinhold, J. A., Mandos, L. A., Rickels, K. & Lohoff, F. W. Pharmacological treatment of generalized anxiety disorder. Expert. Opin. Pharmacother. 12, 2457–2467 (2011).

    Article  CAS  Google Scholar 

  128. 128

    Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Jeffreys, M., Capehart, B. & Friedman, M. J. Pharmacotherapy for posttraumatic stress disorder: review with clinical applications. J. Rehabil. Res. Dev. 49, 703–715 (2012).

    Article  Google Scholar 

  131. 131

    Stein, M., Steckler, T., Lightfoot, J. D., Hay, E. & Goddard, A. W. Pharmacologic treatment of panic disorder. Curr. Top. Behav. Neurosci. 2, 469–485 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Kessler, R. C. et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch. Gen. Psychiatry 51, 8–19 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Ganasen, K. A. & Stein, D. J. Pharmacotherapy of social anxiety disorder. Curr. Top. Behav. Neurosci. 2, 487–503 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Abudy, A., Juven-Wetzler, A. & Zohar, J. Pharmacological management of treatment-resistant obsessive-compulsive disorder. CNS Drugs 25, 585–596 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Varty, G. B., Morgan, C. A., Cohen-Williams, M. E., Coffin, V. L. & Carey, G. J. The gerbil elevated plus-maze I: behavioral characterization and pharmacological validation. Neuropsychopharmacology 27, 357–370 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Shepherd, J. K., Grewal, S. S., Fletcher, A., Bill, D. J. & Dourish, C. T. Behavioural and pharmacological characterisation of the elevated “zero-maze” as an animal model of anxiety. Psychopharmacology 116, 56–64 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Rex, A., Marsden, C. A. & Fink, H. Effect of diazepam on cortical 5-HT release and behaviour in the guinea-pig on exposure to the elevated plus maze. Psychopharmacology 110, 490–496 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Misslin, R., Belzung, C. & Vogel, E. Behavioural validation of a light/dark choice procedure for testing anti-anxiety agents. Behav. Process. 8, 119–132 (1989).

    Article  Google Scholar 

  139. 139

    de Angelis, L. & File, S. E. Acute and chronic effects of three benzodiazepines in the social interaction anxiety test in mice. Psychopharmacology 64, 127–129 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    File, S. E. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J. Neurosci. Methods 2, 219–238 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Thiebot, M. H., Dangoumau, L., Richard, G. & Puech, A. J. Safety signal withdrawal: a behavioural paradigm sensitive to both “anxiolytic” and “anxiogenic” drugs under identical experimental conditions. Psychopharmacology 103, 415–424 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Winslow, J. T. & Insel, T. R. The infant rat separation paradigm: a novel test for novel anxiolytics. Trends Pharmacol. Sci. 12, 402–404 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Vinkers, C. H. et al. Translational aspects of pharmacological research into anxiety disorders: the stress-induced hyperthermia (SIH) paradigm. Eur. J. Pharmacol. 585, 407–425 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Boissier, J. R., Simon, P. & Aron, C. A new method for the rapid screening of minor tranquillisers in mice. Eur. J. Pharmacol. 4, 145–151 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Njung'e, K. & Handley, S. L. Evaluation of marble-burying behavior as a model of anxiety. Pharmacol. Biochem. Behav. 38, 63–67 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Treit, D., Pinel, J. P. & Fibiger, H. C. Conditioned defensive burying: a new paradigm for the study of anxiolytic agents. Pharmacol. Biochem. Behav. 15, 619–626 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Davis, M. Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm. Behav. Neurosci. 100, 814–824 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Geyer, M. A., Petersen, L. R. & Rose, G. J. Effects of serotonergic lesions on investigatory responding by rats in a holeboard. Behav. Neural. Biol. 30, 160–177 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Bodnoff, S. R., Suranyi Cadotte, B., Aitken, D. H., Quirion, R. & Meaney, M. J. The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology 95, 298–302 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Viana, M. B., Tomaz, C. & Graeff, F. G. The elevated T-maze: a new animal model of anxiety and memory. Pharmacol. Biochem. Behav. 49, 549–554 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Espana, J. et al. Intraneuronal β-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer's disease transgenic mice. Biol. Psychiatry 67, 513–521 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Richardson-Jones, J. W. et al. Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety. J. Neurosci. 31, 6008–6018 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Gleason, G. et al. The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety. Proc. Natl Acad. Sci. USA 107, 7592–7597 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Tsetsenis, T., Ma, X. H., Lo, I. L., Beck, S. G. & Gross, C. Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nature Neurosci. 10, 896–902 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Klemenhagen, K. C., Gordon, J. A., David, D. J., Hen, R. & Gross, C. T. Increased fear response to contextual cues in mice lacking the 5-HT1A receptor. Neuropsychopharmacology 31, 101–111 (2005).

    Article  CAS  Google Scholar 

  156. 156

    Li, Q. et al. Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences. J. Neurosci. 24, 10868–10877 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Bailey, S. J. & Toth, M. Variability in the benzodiazepine response of serotonin 5-HT1A receptor null mice displaying anxiety-like phenotype: evidence for genetic modifiers in the 5-HT-mediated regulation of GABAA receptors. J. Neurosci. 24, 6343–6351 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Pattij, T. et al. Autonomic changes associated with enhanced anxiety in 5-HT1A receptor knockout mice. Neuropsychopharmacology 27, 380–390 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Gross, C. et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Sibille, E., Pavlides, C., Benke, D. & Toth, M. Genetic inactivation of the serotonin1A receptor in mice results in downregulation of major GABAA receptor α subunits, reduction of GABAA receptor binding, and benzodiazepine-resistant anxiety. J. Neurosci. 20, 2758–2765 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Ramboz, S. et al. Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc. Natl Acad. Sci. USA 95, 14476–14481 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Parks, C. L., Robinson, P. S., Sibille, E., Shenk, T. & Toth, M. Increased anxiety of mice lacking the serotonin1A receptor. Proc. Natl Acad. Sci. USA 95, 10734–10739 (1998).

    Article  CAS  Google Scholar 

  163. 163

    Heisler, L. K. et al. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl Acad. Sci. USA 95, 15049–15054 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Guilloux, J. P. et al. Characterization of 5-HT1A/1B−/− mice: an animal model sensitive to anxiolytic treatments. Neuropharmacology 61, 478–488 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Mombereau, C., Kawahara, Y., Gundersen, B. B., Nishikura, K. & Blendy, J. A. Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors. Neuropharmacology 59, 468–473 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Bhatnagar, S. et al. Changes in anxiety-related behaviors and hypothalamic–pituitary–adrenal activity in mice lacking the 5-HT-3A receptor. Physiol. Behav. 81, 545–555 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Bhatnagar, S., Nowak, N., Babich, L. & Bok, L. Deletion of the 5-HT3 receptor differentially affects behavior of males and females in the Porsolt forced swim and defensive withdrawal tests. Behav. Brain Res. 153, 527–535 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Narayanan, V. et al. Social defeat: impact on fear extinction and amygdala-prefrontal cortical theta synchrony in 5-HTT deficient mice. PLoS ONE 6, e22600 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Line, S. J. et al. Opposing alterations in anxiety and species-typical behaviours in serotonin transporter overexpressor and knockout mice. Eur. Neuropsychopharmacol. 21, 108–116 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Heiming, R. S. et al. Living in a dangerous world: the shaping of behavioral profile by early environment and 5-HTT genotype. Front. Behav. Neurosci. 3, 26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Wellman, C. L. et al. Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J. Neurosci. 27, 684–691 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Carroll, J. C. et al. Effects of mild early life stress on abnormal emotion-related behaviors in 5-HTT knockout mice. Behav. Genet. 37, 214–222 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Ansorge, M. S., Zhou, M., Lira, A., Hen, R. & Gingrich, J. A. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306, 879–881 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Lira, A. et al. Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol. Psychiatry 54, 960–971 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Holmes, A., Yang, R. J., Lesch, K. P., Crawley, J. N. & Murphy, D. L. Mice lacking the serotonin transporter exhibit 5-HT1A receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology 28, 2077–2088 (2003).

    Article  CAS  Google Scholar 

  176. 176

    Hasegawa, S. et al. Transgenic up-regulation of α-CaMKII in forebrain leads to increased anxiety-like behaviors and aggression. Mol. Brain 2, 6 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Ledent, C. et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388, 674–678 (1997).

    Article  CAS  Google Scholar 

  178. 178

    Lähdesmaki, J. et al. Behavioral and neurochemical characterization of α2a-adrenergic receptor knockout mice. Neuroscience 113, 289–299 (2002).

    Article  Google Scholar 

  179. 179

    Schramm, N. L., McDonald, M. P. & Limbird, L. E. The α2a-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J. Neurosci. 21, 4875–4882 (2001).

    Article  CAS  Google Scholar 

  180. 180

    Okuyama, S. et al. Anxiety-like behavior in mice lacking the angiotensin II type-2 receptor. Brain Res. 821, 150–159 (1999).

    Article  CAS  Google Scholar 

  181. 181

    Ichiki, T. et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature 377, 748–750 (1995).

    Article  CAS  Google Scholar 

  182. 182

    Raber, J. Role of apolipoprotein E in anxiety. Neural Plast. 2007, 91236 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Dubreucq, S. et al. Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice. Neuropsychopharmacology 37, 1885–1900 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Kamprath, K. et al. Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling. Genes Brain Behav. 8, 203–211 (2009).

    Article  CAS  Google Scholar 

  185. 185

    Bura, S. A., Burokas, A., Martin-Garcia, E. & Maldonado, R. Effects of chronic nicotine on food intake and anxiety-like behaviour in CB1 knockout mice. Eur. Neuropsychopharmacol. 20, 369–378 (2010).

    Article  CAS  Google Scholar 

  186. 186

    Tourino, C., Ledent, C., Maldonado, R. & Valverde, O. CB1 cannabinoid receptor modulates 3,4-methylenedioxymethamphetamine acute responses and reinforcement. Biol. Psychiatry 63, 1030–1038 (2008).

    Article  CAS  Google Scholar 

  187. 187

    Kamprath, K. et al. Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J. Neurosci. 26, 6677–6686 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Haller, J., Varga, B., Ledent, C., Barna, I. & Freund, T. F. Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behaviour in mice. Eur. J. Neurosci. 19, 1906–1912 (2004).

    Article  CAS  Google Scholar 

  189. 189

    Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Haller, J., Bakos, N., Szirmay, M., Ledent, C. & Freund, T. F. The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur. J. Neurosci. 16, 1395–1398 (2002).

    Article  CAS  Google Scholar 

  191. 191

    Maccarrone, M. et al. Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour. Eur. J. Neurosci. 15, 1178–1186 (2002).

    Article  Google Scholar 

  192. 192

    Martin, M., Ledent, C., Parmentier, M., Maldonado, R. & Valverde, O. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology 159, 379–387 (2002).

    Article  CAS  Google Scholar 

  193. 193

    Gogos, J. A. et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc. Natl Acad. Sci. USA 95, 9991–9996 (1998).

    Article  CAS  Google Scholar 

  194. 194

    Yamamoto, Y. et al. Increased anxiety behavior in OLETF rats without cholecystokinin-A receptor. Brain Res. Bull. 53, 789–792 (2000).

    Article  CAS  Google Scholar 

  195. 195

    Kobayashi, S., Ohta, M., Miyasaka, K. & Funakoshi, A. Decrease in exploratory behavior in naturally occurring cholecystokinin (CCK)A receptor gene knockout rats. Neurosci. Lett. 214, 61–64 (1996).

    Article  CAS  Google Scholar 

  196. 196

    Abramov, U. et al. Different housing conditions alter the behavioural phenotype of CCK2 receptor-deficient mice. Behav. Brain Res. 193, 108–116 (2008).

    Article  CAS  Google Scholar 

  197. 197

    Miyasaka, K. et al. Anxiety-related behaviors in cholecystokinin-A, B, and AB receptor gene knockout mice in the plus-maze. Neurosci. Lett. 335, 115–118 (2002).

    Article  CAS  Google Scholar 

  198. 198

    Vasar, E. et al. CCKB receptor knockout mice: gender related behavioural differences. Eur. Neuropsychopharmacol. 10 (Suppl. 2), 69 (2000).

    Google Scholar 

  199. 199

    Chen, Q., Nakajima, A., Meacham, C. & Tang, Y. P. Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse. Proc. Natl Acad. Sci. USA 103, 3881–3886 (2006).

    Article  CAS  Google Scholar 

  200. 200

    Kolber, B. J. et al. Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J. Neurosci. 30, 2571–2581 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    van Gaalen, M. M., Stenzel-Poore, M. P., Holsboer, F. & Steckler, T. Effects of transgenic overproduction of CRH on anxiety-like behaviour. Eur. J. Neurosci. 15, 2007–2015 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  202. 202

    Heinrichs, S. C. et al. Anti-sexual and anxiogenic behavioral consequences of corticotropin-releasing factor overexpression are centrally mediated. Psychoneuroendocrinology 22, 215–224 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Stenzel-Poore, M. P., Duncan, J. E., Rittenberg, M. B., Bakke, A. C. & Heinrichs, S. C. CRH overproduction in transgenic mice: behavioral and immune system modulation. Ann. NY Acad. Sci. 780, 36–48 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    Ramesh, T. M., Karolyi, I. J., Nakajima, M., Camper, S. A. & Seasholtz, A. F. Altered physiological and behavioral responses in CRH-binding protein deficient mice. Abstr. Soc. Neurosci. 24, 505 (1998).

    Google Scholar 

  206. 206

    Karolyi, I. J. et al. Altered anxiety and weight gain in corticotropin-releasing hormone-binding protein-deficient mice. Proc. Natl Acad. Sci. USA 96, 11595–11600 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    Refojo, D. et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333, 1903–1907 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Kishimoto, T. et al. Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nature Genet. 24, 415–419 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. 209

    Coste, S. C. et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nature Genet. 24, 403–409 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Bale, T. L. et al. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nature Genet. 24, 410–414 (2000).

    Article  CAS  Google Scholar 

  211. 211

    Umehara, F. et al. Elevated anxiety-like and depressive behavior in Desert hedgehog knockout male mice. Behav. Brain Res. 174, 167–173 (2006).

    Article  Google Scholar 

  212. 212

    Dulawa, S. C., Grandy, D. K., Low, M. J., Paulus, M. P. & Geyer, M. A. Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J. Neurosci. 19, 9550–9556 (1999).

    Article  CAS  Google Scholar 

  213. 213

    Ogawa, S., Lubahn, D. B., Korach, K. S. & Pfaff, D. W. Behavioral effects of estrogen receptor gene disruption in male mice. Proc. Natl Acad. Sci. USA 94, 1476–1481 (1997).

    Article  CAS  Google Scholar 

  214. 214

    Spencer, C. M., Alekseyenko, O., Serysheva, E., Yuva-Paylor, L. A. & Paylor, R. Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome. Genes Brain Behav. 4, 420–430 (2005).

    Article  CAS  Google Scholar 

  215. 215

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

    Article  CAS  Google Scholar 

  216. 216

    Sonner, J. M. et al. α1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear. Mol. Pharmacol. 68, 61–68 (2005).

    Article  CAS  Google Scholar 

  217. 217

    Dixon, C. I., Rosahl, T. W. & Stephens, D. N. Targeted deletion of the GABRA2 gene encoding α2-subunits of GABAA receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates. Pharmacol. Biochem. Behav. 90, 1–8 (2008).

    Article  CAS  Google Scholar 

  218. 218

    Hashemi, E., Sahbaie, P., Davies, M. F., Clark, J. D. & Delorey, T. M. Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites. Brain Res. 1129, 191–199 (2007).

    Article  CAS  Google Scholar 

  219. 219

    Liljelund, P., Ferguson, C., Homanics, G. & Olsen, R. W. Long-term effects of diazepam treatment of epileptic GABAA receptor β3 subunit knockout mouse in early life. Epilepsy Res. 66, 99–115 (2005).

    Article  CAS  Google Scholar 

  220. 220

    Earnheart, J. C. et al. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J. Neurosci. 27, 3845–3854 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. 221

    Homanics, G. E. et al. Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the γ2 subunit of the γ-aminobutyrate type A receptor. Neuropharmacology 38, 253–265 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. 222

    Crestani, F. et al. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nature Neurosci. 2, 833–839 (1999).

    Article  CAS  Google Scholar 

  223. 223

    Chandra, D., Korpi, E. R., Miralles, C. P., De Blas, A. L. & Homanics, G. E. GABAA receptor γ2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines. BMC Neurosci. 6, 30 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. 224

    Mombereau, C. et al. Altered anxiety and depression-related behaviour in mice lacking GABAB(2) receptor subunits. Neuroreport 16, 307–310 (2005).

    Article  CAS  Google Scholar 

  225. 225

    Mombereau, C., Kaupmann, K., van der Putten, H. & Cryan, J. F. Altered response to benzodiazepine anxiolytics in mice lacking GABAB(1) receptors. Eur. J. Pharmacol. 497, 119–120 (2004).

    Article  CAS  Google Scholar 

  226. 226

    Mombereau, C. et al. Genetic and pharmacological evidence of a role for GABAB receptors in the modulation of anxiety- and antidepressant-like behavior. Neuropsychopharmacology 29, 1050–1062 (2004).

    Article  CAS  Google Scholar 

  227. 227

    Sangha, S. et al. Deficiency of the 65 kDa isoform of glutamic acid decarboxylase impairs extinction of cued but not contextual fear memory. J. Neurosci. 29, 15713–15720 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. 228

    Bergado-Acosta, J. R. et al. Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory. Learn. Mem. 15, 163–171 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. 229

    Stork, O., Yamanaka, H., Stork, S., Kume, N. & Obata, K. Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice. Genes Brain Behav. 2, 65–70 (2003).

    Article  CAS  Google Scholar 

  230. 230

    Stork, O. et al. Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65. Brain Res. 865, 45–58 (2000).

    Article  CAS  Google Scholar 

  231. 231

    Kash, S. F., Tecott, L. H., Hodge, C. & Baekkeskov, S. 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 (1999).

    Article  CAS  Google Scholar 

  232. 232

    Chiu, C. S. et al. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J. Neurosci. 25, 3234–3245 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. 233

    Holmes, A. et al. Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze. Neuropsychopharmacology 28, 1031–1044 (2003).

    Article  CAS  Google Scholar 

  234. 234

    Wei, Q. et al. Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional lability. Proc. Natl Acad. Sci. USA 101, 11851–11856 (2004).

    Article  CAS  Google Scholar 

  235. 235

    Labrie, V. & Roder, J. C. The involvement of the NMDA receptor d-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neurosci. Biobehav. Rev. 34, 351–372 (2009).

    Article  CAS  Google Scholar 

  236. 236

    Delawary, M. et al. NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala. Mol. Brain 3, 37 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. 237

    Davis, M. J., Haley, T., Duvoisin, R. M. & Raber, J. Measures of anxiety, sensorimotor function, and memory in male and female mGluR4−/− mice. Behav. Brain Res. 229, 21–28 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  238. 238

    Wu, L. J. et al. Increased anxiety-like behavior and enhanced synaptic efficacy in the amygdala of GluR5 knockout mice. PLoS ONE 2, e167 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. 239

    Linden, A. M. et al. Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. Neuropharmacology 43, 251–259 (2002).

    Article  CAS  Google Scholar 

  240. 240

    Duvoisin, R. M., Villasana, L., Davis, M. J., Winder, D. G. & Raber, J. Opposing roles of mGluR8 in measures of anxiety involving non-social and social challenges. Behav. Brain Res. 221, 50–54 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. 241

    Robbins, M. J. et al. Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Brain Res. 1152, 215–227 (2007).

    Article  CAS  Google Scholar 

  242. 242

    Sparta, D. R., Fee, J. R., Knapp, D. J., Breese, G. R. & Thiele, T. E. Elevated anxiety-like behavior following ethanol exposure in mutant mice lacking neuropeptide Y (NPY). Drug Alcohol Depend. 90, 297–300 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. 243

    Duvoisin, R. M. et al. Increased measures of anxiety and weight gain in mice lacking the group III metabotropic glutamate receptor mGluR8. Eur. J. Neurosci. 22, 425–436 (2005).

    Article  Google Scholar 

  244. 244

    Acevedo, S. F., Pfankuch, T., Ohtsu, H. & Raber, J. Anxiety and cognition in female histidine decarboxylase knockout (Hdc−/−) mice. Behav. Brain Res. 168, 92–99 (2006).

    Article  CAS  Google Scholar 

  245. 245

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

    Article  CAS  Google Scholar 

  246. 246

    Armario, A., Hernandez, J., Bluethmann, H. & Hidalgo, J. IL-6 deficiency leads to increased emotionality in mice: evidence in transgenic mice carrying a null mutation for IL-6. J. Neuroimmunol. 92, 160–169 (1998).

    Article  CAS  Google Scholar 

  247. 247

    Walther, T. et al. Sustained long term potentiation and anxiety in mice lacking the Mas protooncogene. J. Biol. Chem. 273, 11867–11873 (1998).

    Article  CAS  Google Scholar 

  248. 248

    Nakamura, E. et al. 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 (1998).

    Article  CAS  Google Scholar 

  249. 249

    Stork, O. et al. Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. J. Neurobiol. 40, 343–355 (1999).

    Article  CAS  Google Scholar 

  250. 250

    Ross, S. A. et al. Phenotypic characterization of an α4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse. J. Neurosci. 20, 6431–6441 (2000).

    Article  CAS  Google Scholar 

  251. 251

    Ouagazzal, A. M., Moreau, J. L., Pauly-Evers, M. & Jenck, Z. F. Impact of environmental housing conditions on the emotional responses of mice deficient for nociceptin/orphanin FQ peptide precursor gene. Behav. Brain Res. 144, 111–117 (2003).

    Article  CAS  Google Scholar 

  252. 252

    Frisch, C. et al. Superior water maze performance and increase in fear-related behavior in the endothelial nitric oxide synthase-deficient mouse together with monoamine changes in cerebellum and ventral striatum. J. Neurosci. 20, 6694–6700 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. 253

    Köster, A. et al. Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice. Proc. Natl Acad. Sci. USA 96, 10444–10449 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  254. 254

    Gavioli, E. C. et al. Altered anxiety-related behavior in nociceptin/orphanin FQ receptor gene knockout mice. Peptides 28, 1229–1239 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. 255

    Painsipp, E., Herzog, H., Sperk, G. & Holzer, P. Sex-dependent control of murine emotional-affective behaviour in health and colitis by peptide YY and neuropeptide Y. Br. J. Pharmacol. 163, 1302–1314 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. 256

    Bannon, A. W. et al. Behavioral characterization of neuropeptide Y knockout mice. Brain Res. 868, 79–87 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. 257

    Palmiter, R. D., Erickson, J. C., Hollopeter, G., Baraban, S. C. & Schwartz, M. W. Life without neuropeptide Y. Recent Prog. Horm. Res. 53, 163–199 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. 258

    Inui, A. et al. Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y. Proc. Assoc. Am. Physicians 110, 171–182 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259

    Karl, T., Burne, T. H. & Herzog, H. Effect of Y1 receptor deficiency on motor activity, exploration, and anxiety. Behav. Brain Res. 167, 87–93 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. 260

    Konig, M. et al. Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383, 535–538 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. 261

    Osada, T. et al. Increased anxiety and impaired pain response in puromycin-sensitive aminopeptidase gene-deficient mice obtained by a mouse gene-trap method. J. Neurosci. 19, 6068–6078 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. 262

    Zhao, L. et al. Central nervous system-specific knockout of steroidogenic factor 1 results in increased anxiety-like behavior. Mol. Endocrinol. 22, 1403–1415 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. 263

    Chrast, R. et al. Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome. Hum. Mol. Genet. 9, 1853–1864 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. 264

    Sun, Y., Zupan, B., Raaka, B. M., Toth, M. & Gershengorn, M. C. TRH-receptor-type-2-deficient mice are euthyroid and exhibit increased depression and reduced anxiety phenotypes. Neuropsychopharmacology 34, 1601–1608 (2009).

    Article  CAS  Google Scholar 

  265. 265

    Sekiyama, K. et al. Abnormalities in aggression and anxiety in transgenic mice overexpressing activin E. Biochem. Biophys. Res. Commun. 385, 319–323 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. 266

    Dierssen, M. et al. Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction. Neurobiol. Dis. 24, 403–418 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. 267

    Fiore, M. et al. Exploratory and displacement behavior in transgenic mice expressing high levels of brain TNF-α. Physiol. Behav. 63, 571–576 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. 268

    Ehninger, D. & Silva, A. J. Increased levels of anxiety-related behaviors in a Tsc2 dominant negative transgenic mouse model of tuberous sclerosis. Behav. Genet. 41, 357–363 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  269. 269

    Bielsky, I. F., Hu, S. B., Ren, X., Terwilliger, E. F. & Young, L. J. The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron 47, 503–513 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. 270

    Crawley, J. N. & Davis, L. G. Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains. Brain Res. Bull. 8, 609–612 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. 271

    Crawley, J. N. et al. Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132, 107–124 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. 272

    Griebel, G., Belzung, C., Misslin, R. & Vogel, E. The free-exploratory paradigm: an effective method for measuring neophobic behaviour in mice and testing potential neophobia-reducing drugs. Behav. Pharmacol. 4, 637–644 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. 273

    Pobbe, R. L. et al. General and social anxiety in the BTBR T+ tf/J mouse strain. Behav. Brain Res. 216, 446–451 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  274. 274

    Kantor, S., Anheuer, Z. E. & Bagdy, G. High social anxiety and low aggression in Fawn-Hooded rats. Physiol. Behav. 71, 551–557 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. 275

    Kromer, S. A. et al. Identification of glyoxalase-I as a protein marker in a mouse model of extremes in trait anxiety. J. Neurosci. 25, 4375–4384 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. 276

    Salome, N. et al. Reliability of high and low anxiety-related behaviour: influence of laboratory environment and multifactorial analysis. Behav. Brain Res. 136, 227–237 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  277. 277

    Landgraf, R. et al. Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: focus on vasopressin and glyoxalase-I. Neurosci. Biobehav. Rev. 31, 89–102 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. 278

    Commissaris, R. L., Harrington, G. M. & Altman, H. J. Benzodiazepine anti-conflict effects in Maudsley reactive (MR/Har) and non-reactive (MNRA/Har) rats. Psychopharmacology 100, 287–292 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. 279

    Commissaris, R. L., McCloskey, T. C., Harrington, G. M. & Altman, H. J. MR/Har and MNRA/Har Maudsley rat strains: differential response to chlordiazepoxide in a conflict task. Pharmacol. Biochem. Behav. 32, 801–805 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. 280

    Blizard, D. A. & Adams, N. The Maudsley reactive and nonreactive strains: a new perspective. Behav. Genet. 32, 277–299 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  281. 281

    Lopez-Aumatell, R. et al. Unlearned anxiety predicts learned fear: a comparison among heterogeneous rats and the Roman rat strains. Behav. Brain Res. 202, 92–101 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  282. 282

    Yilmazer-Hanke, D. M., Faber-Zuschratter, H., Linke, R. & Schwegler, H. Contribution of amygdala neurons containing peptides and calcium-binding proteins to fear-potentiated startle and exploration-related anxiety in inbred Roman high- and low-avoidance rats. Eur. J. Neurosci. 15, 1206–1218 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  283. 283

    Steimer, T., Driscoll, P. & Schulz, P. E. Brain metabolism of progesterone, coping behaviour and emotional reactivity in male rats from two psychogenetically selected lines. J. Neuroendocrinol. 9, 169–175 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. 284

    McAuley, J. D. et al. Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis. Behav. Brain Res. 204, 162–168 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. 285

    Paré, W. P., Kluczynski, S. M. & Tejani-Butt, S. M. Strain differences in the open field test and the Porsolt forced swim test following antidepressant treatment. Abstr. Soc. Neurosci. 25, 1583 (1999).

    Google Scholar 

  286. 286

    Davis, M., Walker, D. L., Miles, L. & Grillon, C. Phasic versus sustained fear in rats and humans: role of the extended amygdala in fear versus anxiety. Neuropsychopharmacology 35, 105–135 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank S. Beeské for her editorial assistance.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Guy Griebel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Effects of pharmacological agents and phenotypes of genetically-modified animals in tests for anxiety-related behaviors from 1960 to 2012. (PDF 2574 kb)

PowerPoint slides

Glossary

Validity

A feature that is assessed (for a test or model of anxiety) by determining how closely the model or test resembles human anxiety symptoms (known as face validity); by determining whether the model or test reliably responds to clinically efficacious anxiety medications (known as predictive validity); and by determining the degree to which the model or test recruits the same underlying neurobiology as implicated in human anxiety (known as construct validity).

Approach-avoidance conflict tests

Tests that generate anxiety-related behaviours in rodents by posing a conflict between a natural drive to explore a novel place and an inherent tendency to avoid new — particularly well-exposed — areas that may be dangerous.

Pavlovian fear conditioning

A learning process by which neutral environmental stimuli, by virtue of association with a stressful event, evoke anxiety reactions. Fear extinction involves the learned inhibition of these reactions. Abnormalities in fear conditioning and extinction are thought to underlie anxiety disorders, notably specific phobias and post-traumatic stress disorder.

Neural circuitry

A network of interconnected regions of the brain that mediate anxiety, including cortical structures (for example, the prefrontal cortex), limbic structures (for example, the amygdala, lateral septum and hippocampus) and the midbrain (for example, the dorsal raphe).

Anxiety models

Models that generate lasting or permanently heightened anxiety; for example, by subjecting animals to chronic stress or by identifying or engineering 'high-anxiety' rodent strains. By contrast, simple tests or assays only transiently evoke an anxiety-like behaviour.

Intermediate phenotype

A specific behavioural or neural feature of an anxiety disorder that might be more easily modelled in rodents than the whole constellation of symptoms found in an anxiety disorder.

Anxiety traits

Persistent anxiety characteristics that manifest across a variety of situations and are considered to be an enduring feature of an individual.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Griebel, G., Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12, 667–687 (2013). https://doi.org/10.1038/nrd4075

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing