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Genetic animal models of anxiety

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Abstract

The focus of this review is on progress achieved in identifying specific genes conferring risk for anxiety disorders through the use of genetic animal models. We discuss gene-finding studies as well as those manipulating a candidate gene. Both human and animal studies thus far support the genetic complexity of anxiety. Clinical manifestations of these diseases are likely related to multiple genes. While different anxiety disorders and anxiety-related traits all appear to be genetically influenced, it has been difficult to ascertain genetic influences in common. Mouse studies have provisionally mapped several loci harboring genes that affect anxiety-related behavior. The growing array of mutant mice is providing valuable information about how genes and environment interact to affect anxious behavior via multiple neuropharmacological pathways. Classical genetic methods such as artificial selection of rodents for high or low anxiety are being employed. Expression array technologies have as yet not been employed, but can be expected to implicate novel candidates and neurobiological pathways.

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References

  1. Flint J, Corley R (1996) Do animal models have a place in the genetic analysis of quantitative human behavioural traits? J Mol Med 74:515–521

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Gosling SD (2001) From mice to men: what can we learn about personality from animal research? Psychol Bull 127:45–86

    CAS  PubMed  Google Scholar 

  4. Lesch KP (2001) Molecular foundation of anxiety disorders. J Neural Transm 108:717–746

    Article  CAS  PubMed  Google Scholar 

  5. Tarantino LM, Bucan M (2000) Dissection of behavior and psychiatric disorders using the mouse as a model. Hum Mol Genet 9:953–965

    CAS  PubMed  Google Scholar 

  6. Flint J (2002) Animal models of anxiety. In: Plomin R, DeFries JC, Craig I, McGuffin P (eds) Behavioral genetics in the post genomic world. American Psychological Association, New York

  7. Cattell RB (1950) Personality: a systematic theoretical and factual study. McGraw–Hill, New York

  8. Gray JA (1981) A critique of Eysenck's theory of personality. In: Eysenck HJ (ed) A model for personality. Springer, Berlin Heidelberg, New York, pp 246–277

  9. McCrae RR, Costa PT (1990) Personality in adulthood. Guilford, New York

  10. Cloninger CR (1987) A systematic method for clinical description and classification of personality variants. A proposal. Arch Gen Psychiatry 44:573–588

    CAS  PubMed  Google Scholar 

  11. Cloninger CR (1988) A unified biosocial theory of personality and its role in the development of anxiety states: a reply to commentaries. Psychiatr Dev 6:83–120

    CAS  PubMed  Google Scholar 

  12. Plomin R, Owen MJ, McGuffin P (1994) The genetic basis of complex human behaviors. Science 264:1733–1739

    CAS  PubMed  Google Scholar 

  13. Krueger RF (2000) Phenotypic, genetic, and nonshared environmental parallels in the structure of personality: a view from the multidimensional personality questionnaire. J Pers Soc Psychol 79:1057–1067

    Article  CAS  PubMed  Google Scholar 

  14. Tellegen A (1985) Structures of mood and personality and their relevance to assessing anxiety with an emphasis on self–report. In: Tuma AH, Maser JD (eds) Anxiety and the anxiety disorders. Erlbaum, Hillsdale N.J., pp 681–706

  15. Eysenck HJ (1991) Dimensions of personality: 16, 5, or 3? Criteria for a taxonomic paradigm. Personality Individual Differences 12:773–790

    Article  Google Scholar 

  16. Costa PT, McCrae RR (1992) Normal personality assessment in clinical practice: the NEO personality inventory. Psychol Assess 4:5–13

    Article  Google Scholar 

  17. Clark LA, Watson D (1991) Tripartite model of anxiety and depression: psychometric evidence and taxonomic implications. J Abnorm Psychol 100:316–336

    Article  CAS  PubMed  Google Scholar 

  18. Brown TA, Chorpita BF, Barlow DH (1998) Structural relationships among dimensions of the DSM–IV anxiety and mood disorders and dimensions of negative affect, positive affect, and autonomic arousal. J Abnorm Psychol 107:179–192

    Article  CAS  PubMed  Google Scholar 

  19. Eley TC, Stevenson J (1999) Using genetic analyses to clarify the distinction between depressive and anxious symptoms in children. J Abnorm Child Psychol 27:105–114

    CAS  PubMed  Google Scholar 

  20. Cloninger CR, Van Eerdewegh P, Goate A, Edenberg HJ, Blangero J, Hesselbrock V, Reich T, Nurnberger JJ, Schuckit M, Porjesz B, Crowe R, Rice JP, Foroud T, Przybeck TR, Almasy L, Bucholz K, Wu W, Shears S, Carr K, Crose C, Willig C, Zhao J, Tischfield JA, Li TK, Conneally PM (1998) Anxiety proneness linked to epistatic loci in genome scan of human personality traits. Am J Med Genet 81:313–317

    Google Scholar 

  21. Mazzanti CM, Lappalainen J, Long JC, Bengel D, Naukkarinen H, Eggert M, Virkkunen M, Linnoila M, Goldman D (1998) Role of the serotonin transporter promoter polymorphism in anxiety–related traits. Arch Gen Psychiatry 55:936–940

    CAS  PubMed  Google Scholar 

  22. Maier W, Gansicke M, Freyberger HJ, Linz M, Heun R, Lecrubier Y (2000) Generalized anxiety disorder (ICD–10) in primary care from a cross–cultural perspective: a valid diagnostic entity? Acta Psychiatr Scand 101:29–36

    CAS  PubMed  Google Scholar 

  23. Goldberg D (2000) Plato versus Aristotle: categorical and dimensional models for common mental disorders. Compr Psychiatry 41:8–13

    Article  CAS  PubMed  Google Scholar 

  24. Judd LL, Kessler RC, Paulus MP, Zeller PV, Wittchen HU, Kunovac JL (1998) Comorbidity as a fundamental feature of generalized anxiety disorders: results from the National Comorbidity Study (NCS). Acta Psychiatr Scand [Suppl] 393:6–11

    Google Scholar 

  25. Ohayon MM, Shapiro CM, Kennedy SH (2000) Differentiating DSM–IV anxiety and depressive disorders in the general population: comorbidity and treatment consequences. Can J Psychiatry 45:166–172

    CAS  PubMed  Google Scholar 

  26. Marshall RD, Klein DF (1999) Diagnostic classification of anxiety disorders: historical context and implications for neurobiology. In: Charney DS, Nestler EJ, Bunney BS (eds) Neurobiology of mental illness. Oxford University Press, New York, pp 437–450

  27. Brown TA, Di Nardo PA, Lehman CL, Campbell LA (2001) Reliability of DSM–IV anxiety and mood disorders: implications for the classification of emotional disorders. J Abnorm Psychol 110:49–58

    Article  CAS  PubMed  Google Scholar 

  28. Legrand LN, McGue M, Iacono WG (1999) A twin study of state and trait anxiety in childhood and adolescence. J Child Psychol Psychiatry 40:953–958

    Article  CAS  PubMed  Google Scholar 

  29. Horwath E, Adams P, Wickramaratne P, Pine D, Weissman MM (1997) Panic disorder with smothering symptoms: evidence for increased risk in first–degree relatives. Depress Anxiety 6:147–153

    Article  CAS  PubMed  Google Scholar 

  30. Perna G, Caldirola D, Arancio C, Bellodi L (1997) Panic attacks: a twin study. Psychiatry Res 66:69–71

    Article  CAS  PubMed  Google Scholar 

  31. Topolski TD, Hewitt JK, Eaves LJ, Silberg JL, Meyer JM, Rutter M, Pickles A, Simonoff E (1997) Genetic and environmental influences on child reports of manifest anxiety and symptoms of separation anxiety and overanxious disorders: a community–based twin study. Behav Genet 27:15–28

    CAS  PubMed  Google Scholar 

  32. Gustavsson JP, Pedersen NL, Asberg M, Schalling D (1996) Origins of individual differences in anxiety proneness: a twin/adoption study of the anxiety–related scales from the Karolinska Scales of Personality (KSP). Acta Psychiatr Scand 93:460–469

    CAS  PubMed  Google Scholar 

  33. Hudziak JJ, Rudiger LP, Neale MC, Heath AC, Todd RD (2000) A twin study of inattentive, aggressive, and anxious/depressed behaviors. J Am Acad Child Adolesc Psychiatry 39:469–476

    CAS  PubMed  Google Scholar 

  34. Eley TC, Stevenson J (1999) Exploring the covariation between anxiety and depression symptoms: a genetic analysis of the effects of age and sex. J Child Psychol Psychiatry 40:1273–1282

    Article  CAS  PubMed  Google Scholar 

  35. Hewitt JK, Silberg JL, Rutter M, Simonoff E, Meyer JM, Maes H, Pickles A, Neale MC, Loeber R, Erickson MT, Kendler KS, Heath AC, Truett KR, Reynolds CA, Eaves LJ (1997) Genetics and developmental psychopathology. 1. Phenotypic assessment in the Virginia Twin Study of Adolescent Behavioral Development. J Child Psychol Psychiatry 38:943–963

    CAS  PubMed  Google Scholar 

  36. Hettema JM, Neale MC, Kendler KS (2001) A review and meta–analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158:1568–1578

    Article  CAS  PubMed  Google Scholar 

  37. Kendler KS (1996) Major depression and generalised anxiety disorder. Same genes, (partly) different environments––revisited. Br J Psychiatry [Suppl] 30:68–75

    Google Scholar 

  38. Roy MA, Neale MC, Pedersen NL, Mathe AA, Kendler KS (1995) A twin study of generalized anxiety disorder and major depression. Psychol Med 25:1037–1049

    CAS  PubMed  Google Scholar 

  39. Hettema JM, Prescott CA, Kendler KS (2001) A population–based twin study of generalized anxiety disorder in men and women. J Nerv Ment Dis 189:413–420

    Article  CAS  PubMed  Google Scholar 

  40. Jetty PV, Charney DS, Goddard AW (2001) Neurobiology of generalized anxiety disorder. Psychiatr Clin North Am 24:75–97

    CAS  PubMed  Google Scholar 

  41. Villafuerte SM, Del Favero J, Adolfsson R, Souery D, Massat I, Mendlewicz J, Van Broeckhoven C, Claes S (2002) Gene–based SNP genetic association study of the corticotropin–releasing hormone receptor–2 (CRHR2) in major depression. Am J Med Genet 114:222–226

    Article  PubMed  Google Scholar 

  42. Holsboer F (1999) The rationale for corticotropin–releasing hormone receptor (CRH–R) antagonists to treat depression and anxiety. J Psychiatr Res 33:181–214

    CAS  PubMed  Google Scholar 

  43. Karayiorgou M, Sobin C, Blundell ML, Galke BL, Malinova L, Goldberg P, Ott J, Gogos JA (1999) Family–based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive–compulsive disorder. Biol Psychiatry 45:1178–1189

    Article  CAS  PubMed  Google Scholar 

  44. Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, Gogos JA (1997) Genotype determining low catechol–O–methyltransferase activity as a risk factor for obsessive–compulsive disorder. Proc Natl Acad Sci U S A 94:4572–4575

    CAS  PubMed  Google Scholar 

  45. Alsobrook JP, Zohar AH, Leboyer M, Chabane N, Ebstein RP, Pauls DL (2002) Association between the COMT locus and obsessive–compulsive disorder in females but not males. Am J Med Genet 114:116–120

    Article  PubMed  Google Scholar 

  46. Ohara K, Nagai M, Suzuki Y, Ochiai M, Ohara K (1998) No association between anxiety disorders and catechol–O–methyltransferase polymorphism. Psychiatry Res 80:145–148

    Article  CAS  PubMed  Google Scholar 

  47. Katsuragi S, Kunugi H, Sano A, Tsutsumi T, Isogawa K, Nanko S, Akiyoshi J (1999) Association between serotonin transporter gene polymorphism and anxiety–related traits. Biol Psychiatry 45:368–370

    Article  CAS  PubMed  Google Scholar 

  48. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety–related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    CAS  PubMed  Google Scholar 

  49. Nakamura T, Muramatsu T, Ono Y, Matsushita S, Higuchi S, Mizushima H, Yoshimura K, Kanba S, Asai M (1997) Serotonin transporter gene regulatory region polymorphism and anxiety–related traits in the Japanese. Am J Med Genet 74:544–545

    Article  CAS  PubMed  Google Scholar 

  50. Stoltenberg SF, Twitchell GR, Hanna GL, Cook EH, Fitzgerald HE, Zucker RA, Little KY (2002) Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism. Am J Med Genet 114:230–234

    Article  PubMed  Google Scholar 

  51. Lesch KP (2002) Neuroticism and serotonin: a developmental genetic perspective. In: Plomin R, DeFries JC, Craig IW, McGuffin P (eds) Behavioral genetics in the postgenomic era. American Psychological Association, Washington, D.C., pp 389–423

  52. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA, Haghighi F, de Jesus GM, Rassnick H, Preud'homme–Rivelli X, Austin T, Cunjak J, Mick S, Fine LD, Woodley KA, Das K, Maier W, Adams PB, Freimer NB, Klein DF, Gilliam TC (1998) Results of a genome–wide genetic screen for panic disorder. Am J Med Genet 81:139–147

    Article  CAS  PubMed  Google Scholar 

  53. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R, Jr (2001) Genomewide survey of panic disorder. Am J Med Genet 105:105–109

    Article  CAS  PubMed  Google Scholar 

  54. Smoller JW, Acierno JS, Jr, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, Pava JA, Chadwick LH, White C, Bulzacchelli M, Slaugenhaupt SA (2001) Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet 105:195–206

    Article  CAS  PubMed  Google Scholar 

  55. Smoller JW, Rosenbaum JF, Biederman J, Susswein LS, Kennedy J, Kagan J, Snidman N, Laird N, Tsuang MT, Faraone SV, Schwarz A, Slaugenhaupt SA (2001) Genetic association analysis of behavioral inhibition using candidate loci from mouse models. Am J Med Genet 105:226–235

    Article  CAS  PubMed  Google Scholar 

  56. Shekhar A, McCann UD, Meaney MJ, Blanchard DC, Davis M, Frey KA, Liberzon I, Overall KL, Shear MK, Tecott LH, Winsky L (2001) Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders. Psychopharmacology (Berl) 157:327–339

  57. File SE (1997) Animal tests of anxiety. In: Crawley JN, Gerfen CR, McKay R, Rogawski MA, Sibley DR, Skolnick P (eds) Current protocols in neuroscience. Wiley, New York, pp 8.3.1–8.3.15

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

    CAS  PubMed  Google Scholar 

  59. Crawley JN (1999) Evaluating anxiety in rodents. In: Crusio WE, Gerlai RT (eds) Handbook of molecular–genetic techniques for brain and behavior research. Elsevier, Amsterdam, pp 667–673

  60. Davis M (1992) The role of the amygdala in fear–potentiated startle: implications for animal models of anxiety. Trends Pharmacol Sci 13:35–41

    CAS  PubMed  Google Scholar 

  61. Davis M (1997) Neurobiology of fear responses: the role of the amygdala. J Neuropsychiatry Clin Neurosci 9:382–402

    CAS  PubMed  Google Scholar 

  62. Gaalen MM van, Stenzel–Poore MP, Holsboer F, Steckler T (2002) Effects of transgenic overproduction of CRH on anxiety–like behaviour. Eur J Neurosci 15:2007–2015

    Article  PubMed  Google Scholar 

  63. Fendt M, Fanselow MS (1999) The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 23:743–760

    CAS  PubMed  Google Scholar 

  64. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    CAS  PubMed  Google Scholar 

  65. Hall CS (1936) Emotional behavior in the rat. III. The relationship between emotionality and ambulatory activity. J Comp Physiol Psychol 22:345–352

    Google Scholar 

  66. Henderson ND (1967) Prior treatments on open field behavior in mice: a genetic analysis. Animal Behav 15:376

    Google Scholar 

  67. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus–maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167

    CAS  PubMed  Google Scholar 

  68. Lister RG (1987) The use of a plus–maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    CAS  PubMed  Google Scholar 

  69. Trullas R, Skolnick P (1993) Differences in fear motivated behaviors among inbred mouse strains. Psychopharmacology 111:323–331

    CAS  PubMed  Google Scholar 

  70. Rodgers RJ, Cole JC (1993) Influence of social isolation, gender, strain, and prior novelty on plus–maze behaviour in mice. Physiol Behav 54:729–736

    CAS  PubMed  Google Scholar 

  71. Montgomery KC (1958) The relation between fear induced by novel stimulation and exploratory behavior. J Comp Physiol Psychol 48:254–260

    Google Scholar 

  72. Shepherd JK, Grewal SS, Fletcher A, Bill DJ, Dourish CT (1994) Behavioural and pharmacological characterisation of the elevated "zero– maze" as an animal model of anxiety. Psychopharmacology 116:56–64

    CAS  PubMed  Google Scholar 

  73. Crawley JN (1985) Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev 9:37–44

    Google Scholar 

  74. Pratt JA (1992) The neuroanatomical basis of anxiety. Pharmacol Ther 55:149–181

    Article  CAS  PubMed  Google Scholar 

  75. Hyman SE (1998) Brain neurocircuitry of anxiety and fear: implications for clinical research and practice. Biol Psychiatry 44:1201–1203

    Article  CAS  PubMed  Google Scholar 

  76. Charney DS, Bremner JD (1999) The neurobiology of anxiety disorders. In: Charney DS, Nestler EJ, Bunney BS (eds) Neurobiology of mental illness. Oxford University Press, New York, pp 494–517

  77. Sandford JJ, Argyropoulos SV, Nutt DJ (2000) The psychobiology of anxiolytic drugs. 1. Basic neurobiology. Pharmacol Ther 88:197–212

    Article  CAS  PubMed  Google Scholar 

  78. Bremner JD, Krystal JH, Southwick SM, Charney DS (1996) Noradrenergic mechanisms in stress and anxiety. I. Preclinical studies. Synapse 23:28–38

    Article  CAS  PubMed  Google Scholar 

  79. Charney DS, Heninger GR, Breier A (1984) Noradrenergic function in panic anxiety. Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:751–763

    CAS  PubMed  Google Scholar 

  80. Charney DS, Woods SW, Goodman WK, Heninger GR (1987) Neurobiological mechanisms of panic anxiety: biochemical and behavioral correlates of yohimbine–induced panic attacks. Am J Psychiatry 144:1030–1036

    CAS  PubMed  Google Scholar 

  81. Inoue T, Tsuchiya K, Koyama T (1994) Regional changes in dopamine and serotonin activation with various intensity of physical and psychological stress in the rat brain. Pharmacol Biochem Behav 49:911–920

    Article  CAS  PubMed  Google Scholar 

  82. Graeff FG (1993) Role of 5–HT in defensive behavior and anxiety. Rev Neurosci 4:181–211

    Google Scholar 

  83. Graeff FG (1990) Brain defense systems and anxiety. In: Roth M, Burrows GD, Noyes R (eds) Handbook of anxiety. Elsevier, Amsterdam, pp 307–357

  84. Tork I, Hornoug JP (1990) Raphe nuclei and the serotonergic system. In: Paxinos G (ed) The human nervous system. Academic Press, Orlando, pp 1001–1022

  85. Azmitia EC, Whitaker PM (1995) Anatomy, cell biology and plasticity of the serotonergic system: neuropsychopharmacological implications for the actions of psychotropic drugs. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven, New York, pp 443–490

    Google Scholar 

  86. Grove G, Coplan JD, Hollander E (1997) The neuroanatomy of 5–HT dysregulation and panic disorder. J Neuropsychiatry Clin Neurosci 9:198–207

    CAS  PubMed  Google Scholar 

  87. Braestrup C, Squires RF (1978) Brain specific benzodiazepine receptors. Br J Psychiatry 133:249–260

    CAS  PubMed  Google Scholar 

  88. Braestrup C, Nielsen M, Honore T, Jensen LH, Petersen EN (1983) Benzodiazepine receptor ligands with positive and negative efficacy. Neuropharmacology 22:1451–1457

    Article  CAS  PubMed  Google Scholar 

  89. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (1998) International Union of Pharmacology. XV. Subtypes of gamma–aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev 50:291–313

    CAS  PubMed  Google Scholar 

  90. Guidotti A, Baraldi M, Leon A, Costa E (1980) Benzodiazepines: a tool to explore the biochemical and neurophysiological basis of anxiety. Fed Proc 39:3039–3042

    CAS  PubMed  Google Scholar 

  91. Korte SM (2001) Corticosteroids in relation to fear, anxiety and psychopathology. Neurosci Biobehav Rev 25:117–142

    Article  CAS  PubMed  Google Scholar 

  92. Rodgers RJ, Haller J, Holmes A, Halasz J, Walton TJ, Brain PF (1999) Corticosterone response to the plus–maze: high correlation with risk assessment in rats and mice. Physiol Behav 68:47–53

    Article  CAS  PubMed  Google Scholar 

  93. Wood SJ, Toth M (2001) Molecular pathways of anxiety revealed by knockout mice. Mol Neurobiol 23:103–121

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  95. Picciotto MR (1999) Knock–out mouse models used to study neurobiological systems. Crit Rev Neurobiol 13:103–149

    CAS  PubMed  Google Scholar 

  96. Bolivar V, Cook M, Flaherty L (2000) List of transgenic and knockout mice: behavioral profiles. Mamm Genome 11:260–274

    Article  CAS  PubMed  Google Scholar 

  97. Anagnostopoulos AV, Mobraaten LE, Sharp JJ, Davisson MT (2001) Transgenic and knockout databases: behavioral profiles of mouse mutants. Physiol Behav 73:675–689

    Article  CAS  PubMed  Google Scholar 

  98. Liebowitz MR (1999) Update on the diagnosis and treatment of social anxiety disorder. J Clin Psychiatry 60 Suppl 18:22–26

    Google Scholar 

  99. Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Muller U, Aguet M, Babinet C, Shih JC (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766

    CAS  PubMed  Google Scholar 

  100. Kim JJ, Shih JC, Chen K, Chen L, Bao S, Maren S, Anagnostaras SG, Fanselow MS, De Maeyer E, Seif I, Thompson RF (1997) Selective enhancement of emotional, but not motor, learning in monoamine oxidase A–deficient mice. Proc Natl Acad Sci U S A 94:5929–5933

    CAS  PubMed  Google Scholar 

  101. Grimsby J, Toth M, Chen K, Kumazawa T, Klaidman L, Adams JD, Karoum F, Gal J, Shih JC (1997) Increased stress response and β–phenylethylamine in MAOB–deficient mice. Nat Genet 17:206–210

    CAS  PubMed  Google Scholar 

  102. Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M (1998) Catechol–O–methyltransferase–deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A 95:9991–9996

    Article  CAS  PubMed  Google Scholar 

  103. Amara SG, Kuhar MJ (1993) Neurotransmitter transporters: recent progress. Annu Rev Neurosci 16:73–93

    CAS  PubMed  Google Scholar 

  104. Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW, Wang YM, Caron MG (2000) Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci 3:465–471

    Article  CAS  PubMed  Google Scholar 

  105. Bohn LM, Xu F, Gainetdinov RR, Caron MG (2000) Potentiated opioid analgesia in norepinephrine transporter knock–out mice. J Neurosci 20:9040–9045

    CAS  PubMed  Google Scholar 

  106. Amara SG, Arriza JL (1993) Neurotransmitter transporters: three distinct gene families. Curr Opin Neurobiol 3:337–344

    CAS  PubMed  Google Scholar 

  107. Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, Jackson–Lewis V, Przedborski S, Uhl GR (1997) VMAT2 knockout mice: heterozygotes display reduced amphetamine– conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci U S A 94:9938–9943

    Article  CAS  PubMed  Google Scholar 

  108. Wang YM, Gainetdinov RR, Fumagalli F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG (1997) Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19:1285–1296

    Google Scholar 

  109. MacDonald E, Kobilka BK, Scheinin M (1997) Gene targeting––homing in on α2–adrenoceptor–subtype function. Trends Pharmacol Sci 18:211–219

    CAS  PubMed  Google Scholar 

  110. Rohrer DK, Kobilka BK (1998) Insights from in vivo modification of adrenergic receptor gene expression. Annu Rev Pharmacol Toxicol 38:351–373

    Article  CAS  PubMed  Google Scholar 

  111. Altman JD, Trendelenburg AU, MacMillan L, Bernstein D, Limbird L, Starke K, Kobilka BK, Hein L (1999) Abnormal regulation of the sympathetic nervous system in alpha2A– adrenergic receptor knockout mice. Mol Pharmacol 56:154–161

    CAS  PubMed  Google Scholar 

  112. Schramm NL, McDonald MP, Limbird LE (2001) The α2Α–adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J Neurosci 21:4875–4882

    CAS  PubMed  Google Scholar 

  113. Lahdesmaki J, Sallinen J, MacDonald E, Kobilka BK, Fagerholm V, Scheinin M (2002) Behavioral and neurochemical characterization of alpha(2A)–adrenergic receptor knockout mice. Neuroscience 113:289–299

    Article  CAS  PubMed  Google Scholar 

  114. Pineyro G, Blier P (1999) Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 51:533–591

    CAS  PubMed  Google Scholar 

  115. Barnes NM, Sharp T (1999) A review of central 5–HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  CAS  PubMed  Google Scholar 

  116. Bonasera SJ, Tecott LH (2000) Mouse models of serotonin receptor function: toward a genetic dissection of serotonin systems. Pharmacol Ther 88:133–142

    CAS  PubMed  Google Scholar 

  117. Gingrich JA, Hen R (2001) Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology (Berl) 155:1–10

    Google Scholar 

  118. Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, Parsons LH, Tecott LH (1998) Elevated anxiety and antidepressant–like responses in serotonin 5–HT1A receptor mutant mice. Proc Natl Acad Sci U S A 95:15049–15054

    Article  CAS  PubMed  Google Scholar 

  119. Parks CL, Robinson PS, Sibille E, Shenk T, Toth M (1998) Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci U S A 95:10734–10739

    Article  CAS  PubMed  Google Scholar 

  120. Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R (1998) Serotonin receptor 1A knockout: an animal model of anxiety–related disorder. Proc Natl Acad Sci U S A 95:14476–14481

    Article  CAS  PubMed  Google Scholar 

  121. Pattij T, Groenink L, Hijzen T, Oosting R, Maes R, van der GJ, Olivier B (2002) Autonomic changes associated with enhanced anxiety in 5–HT(1A) receptor knockout mice. Neuropsychopharmacology 27:380

    Article  CAS  PubMed  Google Scholar 

  122. Gross C, Santarelli L, Brunner D, Zhuang X, Hen R (2000) Altered fear circuits in 5–HT1A receptor KO mice. Biol Psychiatry 48:1157–1163

    CAS  PubMed  Google Scholar 

  123. Friedman BH, Thayer JF (1998) Autonomic balance revisited: panic anxiety and heart rate variability. J Psychosom Res 44:133–151

    Article  CAS  PubMed  Google Scholar 

  124. Lesch KP (1991) 5–HT1A receptor responsivity in anxiety disorders and depression. Prog Neuropsychopharmacol Biol Psychiatry 15:723–733

    CAS  PubMed  Google Scholar 

  125. Murphy DL, Lesch KP, Aulakh CS, Pigott TA (1991) Serotonin–selective arylpiperazines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans. Pharmacol Rev 43:527–552

    CAS  PubMed  Google Scholar 

  126. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R (2002) Serotonin1A receptor acts during development to establish normal anxiety–like behaviour in the adult. Nature 416:396–400

    Article  CAS  PubMed  Google Scholar 

  127. Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L, Buhot MC, Hen R (1994) Enhanced aggressive behavior in mice lacking 5–HT1B receptor. Science 265:1875–1878

    CAS  PubMed  Google Scholar 

  128. Zhuang X, Gross C, Santarelli L, Compan V, Trillat AC, Hen R (1999) Altered emotional states in knockout mice lacking 5–HT1A or 5–HT1B receptors. Neuropsychopharmacology 21:52S–60S

    CAS  PubMed  Google Scholar 

  129. Ramboz S, Saudou F, Amara DA, Belzung C, Segu L, Misslin R, Buhot MC, Hen R (1996) 5–HT1B receptor knock out––behavioral consequences. Behav Brain Res 73:305–312

    CAS  PubMed  Google Scholar 

  130. Brunner D, Buhot MC, Hen R, Hofer M (1999) Anxiety, motor activation, and maternal–infant interactions in 5HT1B knockout mice. Behav Neurosci 113:587–601

    CAS  PubMed  Google Scholar 

  131. Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672

    CAS  PubMed  Google Scholar 

  132. Malleret G, Hen R, Guillou JL, Segu L, Buhot MC (1999) 5–HT1B receptor knock–out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze. J Neurosci 19:6157–6168

    Google Scholar 

  133. Phillips TJ, Hen R, Crabbe JC (1999) Complications associated with genetic background effects in research using knockout mice. Psychopharmacology 147:5–7

    Google Scholar 

  134. Wright DE, Seroogy KB, Lundgren KH, Davis BM, Jennes L (1995) Comparative localization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain. J Comp Neurol 351:357–373

    CAS  PubMed  Google Scholar 

  135. Tecott LH, Logue SF, Wehner JM, Kauer JA (1998) Perturbed dentate gyrus function in serotonin 5–HT2C receptor mutant mice. Proc Natl Acad Sci U S A 95:15026–15031

    Article  CAS  PubMed  Google Scholar 

  136. Heisler LK, Bajwa P, Tecott LH (1998) Altered anxiety–like behavior in 5–HT2C receptor null mutant mice. Soc Neurosci Abst 24:602

    Google Scholar 

  137. Kennett GA, Whitton P, Shah K, Curzon G (1989) Anxiogenic–like effects of mCPP and TFMPP in animal models are opposed by 5–HT1C receptor antagonists. Eur J Pharmacol 164:445–454

    CAS  PubMed  Google Scholar 

  138. Eison AS, Eison MS (1994) Serotonergic mechanisms in anxiety. Prog Neuropsychopharmacol Biol Psychiatry 18:47–62

    Google Scholar 

  139. Grailhe R, Waeber C, Dulawa SC, Hornung JP, Zhuang X, Brunner D, Geyer MA, Hen R (1999) Increased exploratory activity and altered response to LSD in mice lacking the 5–HT(5A) receptor. Neuron 22:581–591

    CAS  PubMed  Google Scholar 

  140. Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mossner R, Westphal H, Lesch KP (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4–methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter–deficient mice. Mol Pharmacol 53:649–655

    CAS  PubMed  Google Scholar 

  141. Wichems CH, Li Q, Holmes A, Crawley JN, Tjurmina O, Goldman D, Andrews A, Lesch KP, Murphy DL (2000) Mechanisms mediating the increased anxiety–like and excessive responses to stress in mice lacking the serotonin transpoter. Soc Neurosci Abst 26:400

    Google Scholar 

  142. Murphy DL, Li Q, Engel S, Wichems C, Andrews A, Lesch KP, Uhl G (2001) Genetic perspectives on the serotonin transporter. Brain Res Bull 56:487–494

    Article  CAS  PubMed  Google Scholar 

  143. Salichon N, Gaspar P, Upton AL, Picaud S, Hanoun N, Hamon M, De Maeyer E, Murphy DL, Mossner R, Lesch KP, Hen R, Seif I (2001) Excessive activation of serotonin (5–HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5–ht transporter knock–out mice. J Neurosci 21:884–896

    CAS  PubMed  Google Scholar 

  144. Sieghart W (2000) Unraveling the function of GABA(A) receptor subtypes. Trends Pharmacol Sci 21:411–413

    Article  CAS  PubMed  Google Scholar 

  145. Rudolph U, Crestani F, Mohler H (2001) GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol Sci 22:188–194

    CAS  PubMed  Google Scholar 

  146. Erlander MG, Tillakaratne NJ, Feldblum S, Patel N, Tobin AJ (1991) Two genes encode distinct glutamate decarboxylases. Neuron 7:91–100

    CAS  PubMed  Google Scholar 

  147. Martin DL, Martin SB, Wu SJ, Espina N (1991) Regulatory properties of brain glutamate decarboxylase (GAD): the apoenzyme of GAD is present principally as the smaller of two molecular forms of GAD in brain. J Neurosci 11:2725–2731

    CAS  PubMed  Google Scholar 

  148. Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K (1997) Cleft palate and decreased brain gamma–aminobutyric acid in mice lacking the 67–kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A 94:6496–6499

    Article  CAS  PubMed  Google Scholar 

  149. Condie BG, Bain G, Gottlieb DI, Capecchi MR (1997) Cleft palate in mice with a targeted mutation in the gamma–aminobutyric acid–producing enzyme glutamic acid decarboxylase 67. Proc Natl Acad Sci U S A 94:11451–11455

    Article  CAS  PubMed  Google Scholar 

  150. Kash SF, Johnson RS, Tecott LH, Noebels JL, Mayfield RD, Hanahan D, Baekkeskov S (1997) Epilepsy in mice deficient in the 65–kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A 94:14060–14065

    Article  CAS  PubMed  Google Scholar 

  151. Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF (1998) Local GABA circuit control of experience–dependent plasticity in developing visual cortex. Science 282:1504–1508

    CAS  PubMed  Google Scholar 

  152. Kash SF, Tecott LH, Hodge C, Baekkeskov S (1999) Increased anxiety and altered responses to anxiolytics in mice deficient in the 65–kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A 96:1698–1703

    CAS  PubMed  Google Scholar 

  153. McKernan RM, Whiting PJ (1996) Which GABA A–receptor subtypes really occur in the brain? Trends Neurosci 19:139–143

    Google Scholar 

  154. Sur C, Wafford KA, Reynolds DS, Hadingham KL, Bromidge F, Macaulay A, Collinson N, O'Meara G, Howell O, Newman R, Myers J, Atack JR, Dawson GR, McKernan RM, Whiting PJ, Rosahl TW (2001) Loss of the major GABAA receptor subtype in the brain is not lethal in mice. J Neurosci 21:3409–3418

    CAS  PubMed  Google Scholar 

  155. Vicini S, Ferguson C, Prybylowski K, Kralic J, Morrow AL, Homanics GE (2001) GABAA receptor α1 subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J Neurosci 21:3009–3016

    CAS  PubMed  Google Scholar 

  156. Kralic JE, O'Buckley TK, Khisti RT, Hodge CW, Homanics GE, Morrow AL (2002) GABAA receptor α1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43:685–694

    Article  CAS  PubMed  Google Scholar 

  157. Homanics GE, Ferguson C, Quinlan JJ, Daggett J, Snyder K, Lagenaur C, Mi ZP, Wang XH, Grayson DR, Firestone LL (1997) Gene knockout of the α6 subunit of the γ–aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol Pharmacol 51:588–596

    CAS  PubMed  Google Scholar 

  158. Jones A, Korpi ER, McKernan RM, Pelz R, Nusser Z, Makela R, Mellor JR, Pollard S, Bahn S, Stephenson FA, Randall AD, Sieghart W, Somogyi P, Smith AJ, Wisden W (1997) Ligand–gated ion channel subunit partnerships: GABAA receptor α6 subunit gene inactivation inhibits δ subunit expression. J Neurosci 17:1350–1362

    CAS  PubMed  Google Scholar 

  159. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP, Lagenaur C, Tretter V, Sieghart W, Anagnostaras SG, Sage JR, Fanselow MS, Guidotti A, Spigelman I, Li Z, DeLorey TM, Olsen RW, Homanics GE (1999) Attenuated sensitivity to neuroactive steroids in γ–aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci U S A 96:12905–12910

    Article  CAS  PubMed  Google Scholar 

  160. Gunther U, Benson J, Benke D, Fritschy JM, Reyes G, Knoflach F, Crestani F, Aguzzi A, Arigoni M, Lang Y (1995) Benzodiazepine–insensitive mice generated by targeted disruption of the γ2 subunit gene of γ–aminobutyric acid type A receptors. Proc Natl Acad Sci U S A 92:7749–7753

    CAS  PubMed  Google Scholar 

  161. Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP, Belzung C, Fritschy JM, Luscher B, Mohler H (1999) Decreased GABAA–receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci 2:833–839

    CAS  PubMed  Google Scholar 

  162. Homanics GE, Harrison NL, Quinlan JJ, Krasowski MD, Rick CE, de Blas AL, Mehta AK, Kist F, Mihalek RM, Aul JJ, Firestone LL (1999) 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

    Article  CAS  PubMed  Google Scholar 

  163. Wick MJ, Radcliffe RA, Bowers BJ, Mascia MP, Luscher B, Harris RA, Wehner JM (2000) Behavioural changes produced by transgenic overexpression of γ2L and γ2S subunits of the GABAA receptor. Eur J Neurosci 12:2634–2638

    Article  CAS  PubMed  Google Scholar 

  164. Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H (1999) Benzodiazepine actions mediated by specific γ–aminobutyric acidA receptor subtypes. Nature 401:796–800

    Google Scholar 

  165. Löw K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Mohler H, Rudolph U (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134

    PubMed  Google Scholar 

  166. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat Neurosci 3:587–592

    CAS  PubMed  Google Scholar 

  167. Crestani F, Löw K, Keist R, Mandelli M, Möhler H, Rudolph U (2001) Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol 59:442–445

    CAS  PubMed  Google Scholar 

  168. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin–releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12

    CAS  PubMed  Google Scholar 

  169. Bakshi VP, Kalin NH (2000) Corticotropin–releasing hormone and animal models of anxiety: gene–environment interactions. Biol Psychiatry 48:1175–1198

    Article  CAS  PubMed  Google Scholar 

  170. Chalmers DT, Lovenberg TW, Grigoriadis DE, Behan DP, De Souza EB (1996) Corticotrophin–releasing factor receptors: from molecular biology to drug design. Trends Pharmacol Sci 17:166–172

    CAS  PubMed  Google Scholar 

  171. Koob GF, Heinrichs SC (1999) A role for corticotropin releasing factor and urocortin in behavioral responses to stressors. Brain Res 848:141–152

    CAS  PubMed  Google Scholar 

  172. Muglia LJ, Jenkins NA, Gilbert DJ, Copeland NG, Majzoub JA (1994) Expression of the mouse corticotropin–releasing hormone gene in vivo and targeted inactivation in embryonic stem cells. J Clin Invest 93:2066–2072

    CAS  PubMed  Google Scholar 

  173. Muglia L, Jacobson L, Majzoub JA (1996) Production of corticotropin–releasing hormone–deficient mice by targeted mutation in embryonic stem cells. Ann N Y Acad Sci 780:49–59

    CAS  PubMed  Google Scholar 

  174. Dunn AJ, Swiergiel AH (1999) Behavioral responses to stress are intact in CRF–deficient mice. Brain Res 845:14–20

    CAS  PubMed  Google Scholar 

  175. Weninger SC, Dunn AJ, Muglia LJ, Dikkes P, Miczek KA, Swiergiel AH, Berridge CW, Majzoub JA (1999) Stress–induced behaviors require the corticotropin–releasing hormone (CRH) receptor, but not CRH. Proc Natl Acad Sci U S A 96:8283–8288

    CAS  PubMed  Google Scholar 

  176. Stenzel–Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W (1992) Development of Cushing's syndrome in corticotropin–releasing factor transgenic mice. Endocrinology 130:3378–3386

    CAS  PubMed  Google Scholar 

  177. Stenzel–Poore MP, Duncan JE, Rittenberg MB, Bakke AC, Heinrichs SC (1996) CRH overproduction in transgenic mice: behavioral and immune system modulation. Ann N Y Acad Sci 780:36–48

    CAS  PubMed  Google Scholar 

  178. Stenzel–Poore MP, Heinrichs SC, Rivest S, Koob GF, Vale WW (1994) Overproduction of corticotropin–releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J Neurosci 14:2579–2584

    CAS  PubMed  Google Scholar 

  179. Heinrichs SC, Stenzel–Poore MP, Gold LH, Battenberg E, Bloom FE, Koob GF, Vale WW, Pich EM (1996) Learning impairment in transgenic mice with central overexpression of corticotropin–releasing factor. Neuroscience 74:303–311

    Article  CAS  PubMed  Google Scholar 

  180. Heinrichs SC, Min H, Tamraz S, Carmouche M, Boehme SA, Vale WW (1997) Anti–sexual and anxiogenic behavioral consequences of corticotropin– releasing factor overexpression are centrally mediated. Psychoneuroendocrinology 22:215–224

    Article  CAS  PubMed  Google Scholar 

  181. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C, . (1995) Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin–releasing factor. Nature 378:287–292

    PubMed  Google Scholar 

  182. Vetter DE, Li C, Zhao L, Contarino A, Liberman MC, Smith GW, Marchuk Y, Koob GF, Heinemann SF, Vale W, Lee KF (2002) Urocortin–deficient mice show hearing impairment and increased anxiety–like behavior. Nat Genet 31:363–369

    CAS  PubMed  Google Scholar 

  183. Wang X, Su H, Copenhagen LD, Vaishnav S, Pieri F, Shope CD, Brownell WE, De Biasi M, Paylor R, Bradley A (2002) Urocortin–deficient mice display normal stress–induced anxiety behavior and autonomic control but an impaired acoustic startle response. Mol Cell Biol 22:6605–6610

    Article  CAS  PubMed  Google Scholar 

  184. Karolyi IJ, Burrows HL, Ramesh TM, Nakajima M, Lesh JS, Seong E, Camper SA, Seasholtz AF (1999) Altered anxiety and weight gain in corticotropin–releasing hormone-binding protein–deficient mice. Proc Natl Acad Sci U S A 96:11595–11600

    Article  CAS  PubMed  Google Scholar 

  185. Burrows HL, Nakajima M, Lesh JS, Goosens KA, Samuelson LC, Inui A, Camper SA, Seasholtz AF (1998) Excess corticotropin releasing hormone–binding protein in the hypothalamic–pituitary–adrenal axis in transgenic mice. J Clin Invest 101:1439–1447

    CAS  PubMed  Google Scholar 

  186. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF (1998) Corticotropin releasing factor receptor 1–deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093–1102

    CAS  PubMed  Google Scholar 

  187. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, Blanquet V, Steckler T, Holsboer F, Wurst W (1998) Impaired stress response and reduced anxiety in mice lacking a functional corticotropin–releasing hormone receptor 1. Nat Genet 19:162–166

    CAS  PubMed  Google Scholar 

  188. Contarino A, Dellu F, Koob GF, Smith GW, Lee KF, Vale W, Gold LH (1999) Reduced anxiety–like and cognitive performance in mice lacking the corticotropin–releasing factor receptor 1. Brain Res 835:1–9

    Article  CAS  PubMed  Google Scholar 

  189. Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW, Lee KF (2000) Mice deficient for corticotropin–releasing hormone receptor–2 display anxiety–like behaviour and are hypersensitive to stress. Nat Genet 24:410–414

    Article  CAS  PubMed  Google Scholar 

  190. Coste SC, Kesterson RA, Heldwein KA, Stevens SL, Heard AD, Hollis JH, Murray SE, Hill JK, Pantely GA, Hohimer AR, Hatton DC, Phillips TJ, Finn DA, Low MJ, Rittenberg MB, Stenzel P, Stenzel–Poore MP (2000) Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin–releasing hormone receptor–2. Nat Genet 24:403–409

    Article  CAS  PubMed  Google Scholar 

  191. Kishimoto T, Radulovic J, Radulovic M, Lin CR, Schrick C, Hooshmand F, Hermanson O, Rosenfeld MG, Spiess J (2000) Deletion of Crhr2 reveals an anxiolytic role for corticotropin– releasing hormone receptor–2. Nat Genet 24:415–419

    Article  CAS  PubMed  Google Scholar 

  192. Crabbe JC (2001) Use of genetic analyses to refine phenotypes related to alcohol tolerance and dependence. Alcohol Clin Exp Res 25:288–292

    CAS  PubMed  Google Scholar 

  193. Preil J, Muller MB, Gesing A, Reul JM, Sillaber I, van Gaalen MM, Landgrebe J, Holsboer F, Stenzel–Poore M, Wurst W (2001) Regulation of the hypothalamic–pituitary–adrenocortical system in mice deficient for CRH receptors 1 and 2. Endocrinology 142:4946–4955

    CAS  PubMed  Google Scholar 

  194. Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF (2002) Mice deficient for both corticotropin–releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety–like behavior. J Neurosci 22:193–199

    CAS  PubMed  Google Scholar 

  195. Gass P, Reichardt HM, Strekalova T, Henn F, Tronche F (2001) Mice with targeted mutations of glucocorticoid and mineralocorticoid receptors: models for depression and anxiety? Physiol Behav 73:811–825

    Article  CAS  PubMed  Google Scholar 

  196. Pepin MC, Pothier F, Barden N (1992) Impaired type II glucocorticoid–receptor function in mice bearing antisense RNA transgene. Nature 355:725–728

    CAS  PubMed  Google Scholar 

  197. Pepin MC, Pothier F, Barden N (1992) Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Mol Pharmacol 42:991–995

    CAS  PubMed  Google Scholar 

  198. Rochford J, Beaulieu S, Rousse I, Glowa JR, Barden N (1997) Behavioral reactivity to aversive stimuli in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: effects of diazepam and FG–7142. Psychopharmacology (Berl) 132:145–152

    Google Scholar 

  199. Montkowski A, Barden N, Wotjak C, Stec I, Ganster J, Meaney M, Engelmann M, Reul JM, Landgraf R, Holsboer F (1995) Long–term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol 7:841–845

    CAS  PubMed  Google Scholar 

  200. Steckler T, Holsboer F (1999) Enhanced conditioned approach responses in transgenic mice with impaired glucocorticoid receptor function. Behav Brain Res 102:151–163

    Article  CAS  PubMed  Google Scholar 

  201. Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schutz G (1995) Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 9:1608–1621

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  203. DeFries JC, Hegmann JP (1970) Genetic analysis of open–field behavior. In: Elliot RM, MacCorquodale K, Lindzey G, Clark KE (eds) Contributions to behavior–genetic analysis: the mouse as a prototype. Appleton–Century–Crofts, New York, pp 23–56

  204. Dellu F, Contarino A, Simon H, Koob GF, Gold LH (2000) Genetic differences in response to novelty and spatial memory using a two–trial recognition task in mice. Neurobiol Learn Mem 73:31–48

    Article  CAS  PubMed  Google Scholar 

  205. Crusio WE, Abeelen JHF van (2001) The genetic architecture of behavioural responses to novelty in mice. Heredity 56:55–63

    Google Scholar 

  206. Griebel G, Sanger DJ, Perrault G (1997) Genetic differences in the mouse defense test battery. Aggressive Behav 23:19–31

    Article  Google Scholar 

  207. Kopp C, Vogel E, Rettori MC, Delagrange P, Guardiola–Lemaitre B, Misslin R (1999) Effects of melatonin on neophobic responses in different strains of mice. Pharmacol Biochem Behav 63:521–526

    Article  CAS  PubMed  Google Scholar 

  208. Weizman R, Paz L, Backer MM, Amiri Z, Modai I, Pick CG (1999) Mouse strains differ in their sensitivity to alprazolam effect in the staircase test. Brain Res 839:58–65

    CAS  PubMed  Google Scholar 

  209. Gaalen MM van, Steckler T (2000) Behavioural analysis of four mouse strains in an anxiety test battery. Behav Brain Res 115:95–106

    PubMed  Google Scholar 

  210. Avgustinovich DF, Lipina TV, Bondar NP, Alekseyenko OV, Kudryavtseva NN (2000) Features of the genetically defined anxiety in mice. Behav Genet 30:101–109

    Article  CAS  PubMed  Google Scholar 

  211. Griebel G, Belzung C, Perrault G, Sanger DJ (2000) Differences in anxiety–related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology 148:164–170

    CAS  PubMed  Google Scholar 

  212. Cook MN, Williams RW, Flaherty L (2001) Anxiety–related behaviors in the elevated zero–maze are affected by genetic factors and retinal degeneration. Behav Neurosci 115:468–476

    Article  CAS  PubMed  Google Scholar 

  213. Tarantino LM, Gould TJ, Druhan JP, Bucan M (2000) Behavior and mutagenesis screens: the importance of baseline analysis of inbred strains. Mamm Genome 11:555–564

    Article  CAS  PubMed  Google Scholar 

  214. Aguilar R, Gil L, Flint J, Gray JA, Dawson GR, Driscoll P, Gimenez–Llort L, Escorihuela RM, Fernandez–Teruel A, Tobena A (2002) Learned fear, emotional reactivity and fear of heights: a factor analytic map from a large F(2) intercross of Roman rat strains. Brain Res Bull 57:17–26

    Article  PubMed  Google Scholar 

  215. Wall PM, Messier C (2001) Methodological and conceptual issues in the use of the elevated plus– maze as a psychological measurement instrument of animal anxiety–like behavior. Neurosci Biobehav Rev 25:275–286

    CAS  PubMed  Google Scholar 

  216. Bignami G (1965) Selection for high rates and low rates of avoidance conditioning in the rat. Anim Behav 13:221–227

    CAS  PubMed  Google Scholar 

  217. Brush FR, Froehlich JC, Sakellaris PC (1979) Genetic selection for avoidance behavior in the rat. Behav Genet 9:309–316

    CAS  PubMed  Google Scholar 

  218. Driscoll P, Battig K (1982) Behavioral, emotional and neurochemical profile of rats selected for extreme differences in active, two–way avoidance learning. In: Liebich I (ed) Genetics of the brain. Elsevier, Amsterdam, pp 95–123

  219. Brush FR (1991) Genetic determinants of individual differences in avoidance learning: behavioral and endocrine characteristics. Experientia 47:1039–1050

    CAS  PubMed  Google Scholar 

  220. Willig F, M'Harzi M, Bardelay C, Viet D, Delacour J (1991) Roman strains as a psychogenetic model for the study of working memory: behavioral and biochemical data. Pharmacol Biochem Behav 40:7–16

    CAS  PubMed  Google Scholar 

  221. Willig F, M'Harzi M, Delacour J (1991) Contribution of the Roman strains of rats to the elaboration of animal models of memory. Physiol Behav 50:913–919

    CAS  PubMed  Google Scholar 

  222. Castanon N, Perez–Diaz F, Mormede P (1995) Genetic analysis of the relationships between behavioral and neuroendocrine traits in Roman High and Low Avoidance rat lines. Behav Genet 25:371–384

    CAS  PubMed  Google Scholar 

  223. Driscoll P, Escorihuela RM, Fernandez–Teruel A, Giorgi O, Schwegler H, Steimer T, Wiersma A, Corda MG, Flint J, Koolhaas JM, Langhans W, Schulz PE, Siegel J, Tobena A (1998) Genetic selection and differential stress responses. The Roman lines/strains of rats. Ann N Y Acad Sci 851:501–510

    CAS  PubMed  Google Scholar 

  224. Fernandez–Teruel A, Escorihuela RM, Gray JA, Aguilar R, Gil L, Gimenez–Llort L, Tobena A, Bhomra A, Nicod A, Mott R, Driscoll P, Dawson GR, Flint J (2002) A quantitative trait locus influencing anxiety in the laboratory rat. Genome Res 12:618–626

    CAS  PubMed  Google Scholar 

  225. Broadhurst PL (1975) The Maudsley reactive and nonreactive strains of rats: a survey. Behav Genet 5:299–319

    CAS  PubMed  Google Scholar 

  226. Blizard DA (1981) The Maudsley reactive and nonreactive strains: a North American perspective. Behav Genet 11:469–489

    CAS  PubMed  Google Scholar 

  227. Paterson A, Whiting PJ, Gray JA, Flint J, Dawson GR (2001) Lack of consistent behavioural effects of Maudsley reactive and non-reactive rats in a number of animal tests of anxiety and activity. Psychopharmacology 154:336–342

    Google Scholar 

  228. Crabbe JC (1999) Animal models in neurobehavioral genetics: Methods for estimating genetic correlation. In: Mormede P, Jones BC (eds) Neurobehavioral genetics: methods and applications. CRC Press, Boca Raton, Fla., pp 121–138

    Google Scholar 

  229. Blizard DA, Adams N (2002) The Maudsley Reactive and Nonreactive strains: a new perspective. Behav Genet 32:277–299

    PubMed  Google Scholar 

  230. Gray JA, Flint J, Dawson GR, Fulker DW (1999) A strategy to home–in on polygenes influencing susceptibility to anxiety. Hum Psychopharmacol 14:S3–S10

    Article  Google Scholar 

  231. Liebsch G, Montkowski A, Holsboer F, Landgraf R (1998) Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety–related behaviour. Behav Brain Res 94:301–310

    CAS  PubMed  Google Scholar 

  232. Liebsch G, Linthorst AC, Neumann ID, Reul JM, Holsboer F, Landgraf R (1998) Behavioral, physiological, and neuroendocrine stress responses and differential sensitivity to diazepam in two Wistar rat lines selectively bred for high– and low–anxiety–related behavior. Neuropsychopharmacology 19:381–396

    Google Scholar 

  233. Keck ME, Welt T, Wigger A, Renner U, Engelmann M, Holsboer F, Landgraf R (2001) The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats. Eur J Neurosci 13:373–380

    CAS  PubMed  Google Scholar 

  234. Henniger MS, Ohl F, Holter SM, Weissenbacher P, Toschi N, Lorscher P, Wigger A, Spanagel R, Landgraf R (2000) Unconditioned anxiety and social behaviour in two rat lines selectively bred for high and low anxiety–related behaviour. Behav Brain Res 111:153–163

    Article  CAS  PubMed  Google Scholar 

  235. Ohl F, Toschi N, Wigger A, Henniger MS, Landgraf R (2001) Dimensions of emotionality in a rat model of innate anxiety. Behav Neurosci 115:429–436

    CAS  PubMed  Google Scholar 

  236. Landgraf R, Wigger A (2002) High vs low anxiety–related behavior rats: an animal model of extremes in trait anxiety. Behav Genet 32:301–314

    PubMed  Google Scholar 

  237. Overstreet DH (2002) Behavioral characteristics of rat lines selected for differential hypothermic responses to cholinergic or serotonergic agonists. Behav Genet 32:335–348

    PubMed  Google Scholar 

  238. Belknap JK, Dubay C, Crabbe JC, Buck KJ (1997) Mapping quantitative trait loci for behavioral traits in the mouse. In: Blum K, Noble EP (eds) Handbook of psychiatric genetics. CRC Press, Boca Raton, Fla., pp 435–453

  239. Rodriguez LA, Plomin R, Blizard DA, Jones BC, McClearn GE (1994) Alcohol acceptance, preference, and sensitivity in mice. I. Quantitative genetic analysis using BXD recombinant inbred strains. Alcohol Clin Exp Res 18:1416–1422

    CAS  PubMed  Google Scholar 

  240. Moore KJ, Nagle DL (2000) Complex trait analysis in the mouse: the strengths, the limitations and the promise yet to come. Annu Rev Genet 34:653–686

    CAS  PubMed  Google Scholar 

  241. Clement Y, Proeschel MF, Bondoux D, Girard F, Launay JM, Chapouthier G (1997) Genetic factors regulate processes related to anxiety in mice. Brain Res 752:127–135

    Article  CAS  PubMed  Google Scholar 

  242. Flint J, Corley R, DeFries JC, Fulker DW, Gray JA, Miller S, Collins AC (1995) A simple genetic basis for a complex psychological trait in laboratory mice. Science 269:1432–1435

    CAS  PubMed  Google Scholar 

  243. Gershenfeld HK, Neumann PE, Mathis C, Crawley JN, Li X, Paul SM (1997) Mapping quantitative trait loci for open–field behavior in mice. Behav Genet 27:201–210

    CAS  PubMed  Google Scholar 

  244. Turri MG, Talbot CJ, Radcliffe RA, Wehner JM, Flint J (1999) High–resolution mapping of quantitative trait loci for emotionality in selected strains of mice. Mamm Genome 10:1098–1101

    Article  CAS  PubMed  Google Scholar 

  245. Talbot CJ, Nicod A, Cherny SS, Fulker DW, Collins AC, Flint J (1999) High–resolution mapping of quantitative trait loci in outbred mice. Nat Genet 21:305–308

    Article  CAS  PubMed  Google Scholar 

  246. Gershenfeld HK, Paul SM (1997) Mapping quantitative trait loci for fear–like behaviors in mice. Genomics 46:1–8

    Article  CAS  PubMed  Google Scholar 

  247. Turri MG, Henderson ND, DeFries JC, Flint J (2001) Quantitative trait locus mapping in laboratory mice derived from a replicated selection experiment for open–field activity. Genetics 158:1217–1226

    CAS  PubMed  Google Scholar 

  248. Turri MG, Datta SR, DeFries J, Henderson ND, Flint J (2001) QTL analysis identifies multiple behavioral dimensions in ethological tests of anxiety in laboratory mice. Curr Biol 11:725–734

    Article  CAS  PubMed  Google Scholar 

  249. Moisan MP, Courvoisier H, Bihoreau MT, Gauguier D, Hendley ED, Lathrop M, James MR, Mormede P (1996) A major quantitative trait locus influences hyperactivity in the WKHA rat. Nat Genet 14:471–473

    CAS  PubMed  Google Scholar 

  250. Ramos A, Berton O, Mormede P, Chaouloff F (1997) A multiple–test study of anxiety–related behaviours in six inbred rat strains. Behav Brain Res 85:57–69

    CAS  PubMed  Google Scholar 

  251. Ramos A, Moisan MP, Chaouloff F, Mormede C, Mormede P (1999) Identification of female–specific QTLs affecting an emotionality–related behavior in rats. Mol Psychiatry 4:453–462

    Article  CAS  PubMed  Google Scholar 

  252. Sayah DM, Khan AH, Gasperoni TL, Smith DJ (2000) A genetic screen for novel behavioral mutations in mice. Mol Psychiatry 5:369–377

    Article  CAS  PubMed  Google Scholar 

  253. Belknap JK, Hitzemann R, Crabbe JC, Phillips TJ, Buck KJ, Williams RW (2001) QTL analysis and genomewide mutagenesis in mice: complementary genetic approaches to the dissection of complex traits. Behav Genet 31:5–15

    Article  CAS  PubMed  Google Scholar 

  254. Nadeau JH, Frankel WN (2000) The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nat Genet 25:381–384

    Article  CAS  PubMed  Google Scholar 

  255. Sibille E, Hen R (2001) Serotonin(1A) receptors in mood disorders: a combined genetic and genomic approach. Behav Pharmacol 12:429–438

    CAS  PubMed  Google Scholar 

  256. Fehr C, Grintschuk N, Szegedi A, Anghelescu I, Klawe C, Singer P, Hiemke C, Dahmen N (2000) The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy. Psychiatry Res 97:1–10

    Article  CAS  PubMed  Google Scholar 

  257. Catalano M (1999) The challenges of psychopharmacogenetics. Am J Hum Genet 65:606–610

    Article  CAS  PubMed  Google Scholar 

  258. Pickar D, Rubinow K (2001) Pharmacogenomics of psychiatric disorders. Trends Pharmacol Sci 22:75–83

    Article  CAS  PubMed  Google Scholar 

  259. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA (2002) Evidence for a susceptibility locus for panic disorder near the catechol–O–methyltransferase gene on chromosome 22. Biol Psychiatry 51:591–601

    Article  CAS  PubMed  Google Scholar 

  260. Segman RH, Cooper–Kazaz R, Macciardi F, Goltser T, Halfon Y, Dobroborski T, Shalev AY (2002) Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 7:903–907

    Article  CAS  PubMed  Google Scholar 

  261. Billett EA, Richter MA, Sam F, Swinson RP, Dai XY, King N, Badri F, Sasaki T, Buchanan JA, Kennedy JL (1998) Investigation of dopamine system genes in obsessive–compulsive disorder. Psychiatr Genet 8:163–169

    CAS  PubMed  Google Scholar 

  262. Nakamura M, Ueno S, Sano A, Tanabe H (1999) Polymorphisms of the human homologue of the Drosophila white gene are associated with mood and panic disorders. Mol Psychiatry 4:155–162

    Article  CAS  PubMed  Google Scholar 

  263. Di Bella D, Cavallini MC, Bellodi L (2002) No association between obsessive–compulsive disorder and the 5–HT(1Dbeta) receptor gene. Am J Psychiatry 159:1783–1785

    Article  PubMed  Google Scholar 

  264. Golimbet VE, Alfimova MV, Manandyan KK, Mitushina NG, Abramova LI, Kaleda VG, Oleichik IV, Yurov Y, Trubnikov VI (2002) 5HTR2A gene polymorphism and personality traits in patients with major psychoses. Eur Psychiatry 17:24–28

    Article  CAS  PubMed  Google Scholar 

  265. Stein MB, Chartier MJ, Kozak MV, King N, Kennedy JL (1998) Genetic linkage to the serotonin transporter protein and 5HT2A receptor genes excluded in generalized social phobia. Psychiatry Res 81:283–291

    Article  CAS  PubMed  Google Scholar 

  266. Cavallini MC, Di Bella D, Siliprandi F, Malchiodi F, Bellodi L (2002) Exploratory factor analysis of obsessive–compulsive patients and association with 5–HTTLPR polymorphism. Am J Med Genet 114:347–353

    Article  PubMed  Google Scholar 

  267. Billett EA, Richter MA, King N, Heils A, Lesch KP, Kennedy JL (1997) Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Mol Psychiatry 2:403–406

    Article  CAS  PubMed  Google Scholar 

  268. Deckert J, Catalano M, Heils A, Di Bella D, Friess F, Politi E, Franke P, Nothen MM, Maier W, Bellodi L, Lesch KP (1997) Functional promoter polymorphism of the human serotonin transporter: lack of association with panic disorder. Psychiatr Genet 7:45–47

    CAS  PubMed  Google Scholar 

  269. Hamilton SP, Heiman GA, Haghighi F, Mick S, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA (1999) Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder. Psychiatr Genet 9:1–6

    CAS  PubMed  Google Scholar 

  270. Crowe RR, Wang Z, Noyes R, Jr., Albrecht BE, Darlison MG, Bailey ME, Johnson KJ, Zoega T (1997) Candidate gene study of eight GABAA receptor subunits in panic disorder. Am J Psychiatry 154:1096–1100

    CAS  PubMed  Google Scholar 

  271. Deckert J, Nothen MM, Franke P, Delmo C, Fritze J, Knapp M, Maier W, Beckmann H, Propping P (1998) Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 3:81–85

    CAS  PubMed  Google Scholar 

  272. Kennedy JL, Bradwejn J, Koszycki D, King N, Crowe R, Vincent J, Fourie O (1999) Investigation of cholecystokinin system genes in panic disorder. Mol Psychiatry 4:284–285

    CAS  PubMed  Google Scholar 

  273. Hattori E, Ebihara M, Yamada K, Ohba H, Shibuya H, Yoshikawa T (2001) Identification of a compound short tandem repeat stretch in the 5'–upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia. Mol Psychiatry 6:465–470

    Article  CAS  PubMed  Google Scholar 

  274. Wang Z, Valdes J, Noyes R, Zoega T, Crowe RR (1998) Possible association of a cholecystokinin promotor polymorphism (CCK–36CT) with panic disorder. Am J Med Genet 81:228–234

    Article  CAS  PubMed  Google Scholar 

  275. Prichard Z, Jorm AF, Prior M, Sanson A, Smart D, Zhang Y, Huttley G, Easteal S (2002) Association of polymorphisms of the estrogen receptor gene with anxiety–related traits in children and adolescents: a longitudinal study. Am J Med Genet 114:169–176

    Article  PubMed  Google Scholar 

  276. Sibille E, Pavlides C, Benke D, Toth M (2000) 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

    Google Scholar 

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Acknowledgements

This work was supported by US National Institutes of Health grants AA12439, AA10760, AA13478, AA13519, AA12714, and DA05228; and by the US Department of Veterans Affairs (D. Finn, J. Crabbe). We are very thankful to William Hoffman, MD, PhD, for his comments on the manuscript.

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Authors and Affiliations

  1. Portland Alcohol Research Center, Department of Veterans Affairs Medical Center and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA

    Deborah A. Finn, Mark T. Rutledge-Gorman & John C. Crabbe

  2. VA Medical Center, Research Service, R & D–49, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA

    Deborah A. Finn

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  1. Deborah A. Finn
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  2. Mark T. Rutledge-Gorman
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  3. John C. Crabbe
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Correspondence to Deborah A. Finn.

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Finn, D.A., Rutledge-Gorman, M.T. & Crabbe, J.C. Genetic animal models of anxiety. Neurogenetics 4, 109–135 (2003). https://doi.org/10.1007/s10048-003-0143-2

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