Genetic approaches to the study of anxiety

Annual Review of Neuroscience

Volumn 27, Issue , 2004, Pages 193-222

  Gordon, Joshua A ^a   Hen, Rene ^a  

^a NEW YORK STATE PSYCHIATRIC INSTITUTE   (United States)

Author keywords

Benzodiazepines; Fear; GABA; Knockout mouse; Serotonin

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; BENZODIAZEPINE; CORTICOTROPIN RELEASING FACTOR RECEPTOR; PROTEIN KINASE C EPSILON; SEROTONIN 1A RECEPTOR;

ANXIETY; ANXIETY DISORDER; FEAR; FUNCTIONAL ANATOMY; GENE EXPRESSION; HEREDITY; HUMAN; KNOCKOUT MOUSE; MATERNAL BEHAVIOR; MATERNAL DEPRIVATION; MOLECULAR GENETICS; NONHUMAN; PRIORITY JOURNAL; REVIEW; STRAIN DIFFERENCE; TISSUE SPECIFICITY; TRANSGENIC MOUSE;

ANIMALS; ANXIETY DISORDERS; BRAIN; BRAIN CHEMISTRY; CHROMOSOME MAPPING; DISEASE MODELS, ANIMAL; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MICE; MOLECULAR BIOLOGY; RECEPTORS, NEUROTRANSMITTER;

EID: 3943092619     PISSN: 0147006X     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.neuro.27.070203.144212     Document Type: Review

References (213)

1. 2 intercross of roman rat strains. Brain Res. Bull. 57:17-26
2. Alsobrook JP 2nd, 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. 114:116-20
3. Ammassari-Teule M, Restivo L, Pietteur V, Passino E. 2001. Learning about the context in genetically-defined mice. Behav. Brain Res. 125:195-204
4. Anisman H, Zaharia MD, Meaney MJ, Merali Z. 1998. Do early-life events permanently alter behavioral and hormonal responses to stressors? Int. J. Dev. Neurosci. 16:149-64
5. Atack JR. 2003. Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr. Drug Target. CNS Neurol. Disord. 2:213-32
6. Auerbach J, Geller V, Lezer S, Shinwell E, Belmaker RH, et al. 1999. Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants. Mol. Psychiatry 4:369-73
7. Avgustinovich DF, Lipina TV, Bondar NP, Alekseyenko OV, Kudryavtseva NN. 2000. Features of the genetically defined anxiety in mice. Behav. Genet. 30:101-9
8. Bale TL, Contarino A, Smith GW, Chan R, Gold LH, et al. 2000. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat. Genet. 24:410-14
9. 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. 22:193-99
10. Balogh SA, Wehner JM. 2003. Inbred mouse strain differences in the establishment of long-term fear memory. Behav. Brain Res. 140:97-106
11. Baulieu EE, Robel P, Schumacher M. 2001. Neurosteroids: beginning of the story. Int. Rev. Neurobiol. 46:1-32
12. Beck CH, Fibiger HC. 1995. Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment. J. Neurosci. 15:709-20
13. Belknap JK, Dubay C, Crabbe JC, Buck KJ. 1997. Mapping quantitative trait loci for behavioral traits in the mouse. In Handbook of Psychiatric Genetics, ed. K Blum, EP Noble, pp. 435-53. Boca Raton, FL: CRC Press
14. Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, et al. 2002. Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol. Psychiatry 7:118-22
15. Bicikova M, Tallova J, Hill M, Krausova Z, Hampl R. 2000. Serum concentrations of some neuroactive steroids in women suffering from mixed anxiety-depressive disorder. Neurochem. Res. 25:1623-27
16. Bodnoff SR, Suranyi-Cadotte B, Aitken DH, Quirion R, Meaney MJ. 1988. The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology (Berl.) 95:298-302
17. Bodnoff SR, Suranyi-Cadotte B, Quirion R, Meaney MJ. 1989. A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety. Psychopharmacology (Berl.) 97:277-79
18. Bolivar VJ, Pooler O, Flaherty L. 2001. Inbred strain variation in contextual and cued fear conditioning behavior. Mamm. Genome 12:651-56
19. Borsini F, Podhoma J, Marazziti D. 2002. Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology (Berl.) 163:121-41
20. Bowers BJ, Collins AC, Tritto T, Wehner JM. 2000. Mice lacking PKC gamma exhibit decreased anxiety. Behav. Genet. 30:111-21
21. Broadhurst PL. 1975. The Maudsley reactive and nonreactive strains of rats: a survey. Behav. Genet. 5:299-319
22. Buffett-Jerrott SE, Stewart SH. 2002. Cognitive and sedative effects of benzodiazepine use. Curr. Pharm. Des. 8:45-58
23. Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM, Meaney MJ. 1998. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc. Natl. Acad. Sci. USA 95:5335-40
24. Canto-de-Souza A, Luiz Nunes-de-Souza R, Rodgers RJ. 2002. Anxiolytic-like effect of WAY-100635 microinfusions into the median (but not dorsal) raphe nucleus in mice exposed to the plus-maze: influence of prior test experience. Brain Res. 928:50-59
25. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, et al. 2003. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386-89
26. Champoux M, Bennett A, Shannon C, Higley JD, Lesch KP, Suomi SJ. 2002. Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Mol. Psychiatry 7:1058-63
27. Chang FC, Opp MR. 2001. Corticotropin-releasing hormone (CRH) as a regulator of waking. Neurosci. Biobehav. Rev. 25:445-53
28. Chaouloff F, Castanon N, Mormede P. 1994. Paradoxical differences in animal models of anxiety among the roman rat lines. Neurosci. Lett. 182:217-21
29. Charney DS, Drevets WC. 2002. The neurobiological basis of anxiety disorders. See Davis et al. 2002, pp. 901-30
30. Chen C, Rainnie DG, Greene RW, Tonegawa S. 1994. Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II. Science 266:291-94
31. Clark MS, Kaiyala KJ. 2003. Role of corticotropin-releasing factor family peptides and receptors in stress-related psychiatric disorders. Semin. Clin. Neuropsychiatry 8:119-36
32. Clement Y, Calatayud F, Belzung C. 2002. Genetic basis of anxiety-like behaviour: a critical review. Brain Res. Bull. 57:57-71
33. Clement Y, Proeschel MF, Bondoux D, Girard F, Launay JM, Chapouthier G. 1997. Genetic factors regulate processes related to anxiety in mice. Brain Res. 752:127-35
34. Cohen RM, Kang A, Gulick C. 2001. Quantitative trait loci affecting the behavior of A/J and CBA/J intercross mice in the elevated plus maze. Mamm. Genome 12:501-7
35. Collins I, Moyes C, Davey WB, Rowley M, Bromidge FA, et al. 2002. 3-heteroaryl-2- pyridones: benzodiazepine site ligands with functional selectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels. J. Med. Chem. 45:1887-900
36. Conti LH, Maciver CR, Ferkany JW, Abreu ME. 1990. Footshock-induced freezing behavior in rats as a model for assessing anxiolytics. Psychopharmacology (Berl.) 102:492-97
37. 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. 115:468-76
38. Coste SC, Kesterson RA, Heldwein KA, Stevens SL, Heard AD, et al. 2000. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat. Genet. 24:403-9
39. Crawley JN, Davis LG. 1982. Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains. Brain Res. Bull. 8:609-12
40. Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, et al. 2002. Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc. Natl. Acad. Sci. USA 99:8980-85
41. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R Jr. 2001. Genomewide survey of panic disorder. Am. J. Med. Genet. 105:105-9
42. Cruz AP, Frei F, Graeff FG. 1994. Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol. Biochem. Behav. 49:171-76
43. Davis KL, Charney DS, Coyle JT, Nemeroff C, eds. 2002. Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia: Lippincott Williams and Wilkins
44. Davis M. 1979. Diazepam and flurazepam: effects on conditioned fear as measured with the potentiated startle paradigm. Psychopharmacology (Berl.) 62:1-7
45. Davis M. 1998. Are different parts of the extended amygdala involved in fear versus anxiety? Biol. Psychiatry 44:1239-47
46. Davis M, Walker DL, Myers KM. 2003. Role of the amygdala in fear extinction measured with potentiated startle. Ann. NY Acad. Sci. 985:218-32
47. Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, et al. 1999. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum. Mol. Genet. 8:621-24
48. 1DB receptor gene. Am. J. Psychiatry 159:1783-85
49. Drolet G, Rivest S. 2001. Corticotropin-releasing hormone and its receptors; an evaluation at the transcription level in vivo. Peptides 22:761-67
50. Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA. 1999. Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J. Neurosci. 19:9550-56
51. Dunn AJ, Swiergiel AH. 1999. Behavioral responses to stress are intact in CRF-deficient mice. Brain Res. 845:14-20
52. Eckart K, Jahn O, Radulovic J, Radulovic M, Blank T, et al. 2002. Pharmacology and biology of corticotropin-releasing factor (CRF) receptors. Recept. Channels 8:163-77
53. Eckart K, Radulovic J, Radulovic M, Jahn O, Blank T, et al. 1999. Actions of CRF and its analogs. Curr. Med. Chem. 6:1035-53
54. Falls WA, Carlson S, Turner JG, Willott JF. 1997. Fear-potentiated startle in two strains of inbred mice. Behav. Neurosci. 111:855-61
55. Fernandez-Teruel A, Escorihuela RM, Gray JA, Aguilar R, Gil L, et al. 2002. A quantitative trait locus influencing anxiety in the laboratory rat. Genome Res. 12:618-26
56. File SE. 1996. Recent developments in anxiety, stress, and depression. Pharmacol. Biochem. Behav. 54:3-12
57. Finn CT, Smoller JW. 2001. The genetics of panic disorder. Curr. Psychiatry Rep. 3:131-37
58. Finn DA, Rutledge-Gorman MT, Crabbe JC. 2003. Genetic animal models of anxiety. Neurogenetics 4:109-35
59. Flint J. 2003. Animal models of anxiety and their molecular dissection. Semin. Cell Dev. Biol. 14:37-42
60. Flint J, Corley R, DeFries JC, Fulker DW, Gray JA, et al. 1995. A simple genetic basis for a complex psychological trait in laboratory mice. Science 269:1432-35
61. Francis D, Diorio J, Liu D, Meaney MJ. 1999. Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286:1155-58
62. Francis DD, Szegda K, Campbell G, Martin WD, Insel TR. 2003. Epigenetic sources of behavioral differences in mice. Nat. Neurosci. 6:445-46
63. Frankland PW, O'Brien C, Ohno M, Kirkwood A, Silva AJ. 2001. Alpha-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411:309-13
64. Frisch A, Michaelovsky E, Rockah R, Amir I, Hermesh H, et al. 2000. Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways. Eur. Neuropsychopharmacol. 10:205-9
65. A-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359:154-94
66. Fyer AJ, Mannuzza S, Chapman TF, Martin LY, Klein DF. 1995. Specificity in familial aggregation of phobic disorders. Arch. Gen. Psychiatry 52:564-73
67. Gelernter J, Page GP, Bonvicini K, Woods SW, Pauls DL, Kruger S. 2003. A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan. Mol. Psychiatry 8:71-82
68. Gershenfeld HK, Paul SM. 1998. Towards a genetics of anxious temperament: from mice to men. Acta Psychiatr. Scand. Suppl. 393:56-65
69. Goldberg J, True WR, Eisen SA, Henderson WG. 1990. A twin study of the effects of the Vietnam War on posttraumatic stress disorder. JAMA 263:1227-32
70. Gordon JA. 2002. Anxiolytic drug targets: beyond the usual suspects. J. Clin. Invest. 110:915-17
71. Gorman JM, Kent JM, Coplan JD. 2002. Current and emerging therapeutics of anxiety and stress disorders. See Davis et al. 2002, pp. 967-80
72. Goto SH, Conceicao IM, Ribeiro RA, Frussa-Filho R. 1993. Comparison of anxiety measured in the elevated plus-maze, open-field and social interaction tests between spontaneously hypertensive rats and wistar EPM-1 rats. Br. J. Med. Biol. Res. 26:965-69
73. Gould E. 1999. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 21:46S-51
74. Gratacos M, Nadal M, Martin-Santos R, Pujana MA, Gago J, et al. 2001. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell 106:367-79
75. Gray JA, McNaughton N. 2000. The Neuropsychology of Anxiety. New York: Oxford Univ. Press. 424 pp.
76. Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL. 1999. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am. J. Med. Genet. 88:83-87
77. Griebel G. 1995. 5-hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research. Pharmacol. Ther. 65:319-95
78. 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 (Berl.) 148:164-70
79. Griebel G, Perrault G, Simiand J, Cohen C, Granger P, et al. 2001. S1651498: an anxioselective compound with functional selectivity for alpha2- and alpha3-containing gamma-aminobutyric acid(A) (GABA(A)) receptors. J. Pharmacol. Exp. Ther. 298:753-68
80. A receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms. CNS Drug Rev. 9:3-20
81. Grillon C, Ameli R, Goddard A, Woods SW, Davis M. 1994. Baseline and fear-potentiated startle in panic disorder patients. Biol. Psychiatry 35:431-39
82. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, et al. 2002. Serotonin 1A receptor acts during development to establish normal anxiety-like behavior in the adult. Nature 416:396-400
83. Gustavsson JP, Nothen MM, Jonsson EG, Neidt H, Forslund K, et al. 1999. No association between serotonin transporter gene polymorphisms and personality traits. Am. J. Med. Genet. 88:430-36
84. Hamilton SP, Fyer AJ, Durner M, Heiman GA, Baisre de Leon A, et al. 2003. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc. Natl. Acad. Sci. USA 100:2550-55
85. Hamilton SP, Heiman GA, Haghighi F, Mick S, Klein DF, et al. 1999. Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder. Psychiatr. Genet. 9:1-6
86. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, et al. 2002. Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol. Psychiatry 51:591-601
87. Hamilton SP, Slager SL, Heiman GA, Haghighi F, Klein DF, et al. 2000. No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase- A gene and panic disorder. Mol. Psychiatry 5:465-66
88. Hanna GL, Veenstra-VanderWeele J, Cox NJ, Boehnke M, Himle JA, et al. 2002. Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. Am. J. Med. Genet. 114:541-52
89. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, et al. 2002. Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400-3
90. 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 22:215-24
91. Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, et al. 1998. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl. Acad. Sci. USA 95:15049-54
92. Hettema JM, Annas P, Neale MC, Kendler KS, Fredrikson M. 2003. A twin study of the genetics of fear conditioning. Arch. Gen. Psychiatry 60:702-8
93. Hettema JM, Neale MC, Kendler KS. 2001a. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am. J. Psychiatry 158:1568-78
94. Hettema JM, Prescott CA, Kendler KS. 2001b. A population-based twin study of generalized anxiety disorder in men and women. J. Nerv. Ment. Dis. 189:413-20
95. Hodge CW, Mehmert KK, Kelley SP, McMahon T, Haywood A, et al. 1999. Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCε. Nat. Neurosci. 2:997-1002
96. Hodge CW, Raber J, McMahon T, Walter H, Sanchez-Perez AM, et al. 2002. Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon. J. Clin. Invest. 110:1003-10
97. Holmes A. 2001. Targeted gene mutation approaches to the study of anxiety-like behavior in mice. Neurosci. Biobehav. Rev. 25:261-73
98. Howe DG, Wiley JC, McKnight GS. 2002. Molecular and behavioral effects of a null mutation in all PKA C beta isoforms. Mol. Cell. Neurosci. 20:515-24
99. Huot RL, Thrivikraman KV, Meaney MJ, Plotsky PM. 2001. Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in long evans rats and reversal with antidepressant treatment. Psychopharmacology (Berl.) 158:366-73
100. Inoue T, Hashimoto S, Tsuchiya K, Izumi T, Ohmori T, Koyama T. 1996. Effect of citalopram, a selective serotonin reuptake inhibitor, on the acquisition of conditioned freezing. Eur. J. Pharmacol. 311:1-6
101. Inui A, Okita M, Nakajima M, Momose K, Ueno N, et al. 1998. Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y. Proc. Assoc. Am. Physicians 110:171-82
102. Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, et al. 1998. An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms. Mol. Psychiatry 3:449-51
103. Kalinichev M, Easterling KW, Plotsky PM, Holtzman SG. 2002. Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats. Pharmacol. Biochem. Behav. 73:131-40
104. Karayiorgou M, Sobin C, Blundell ML, Galke BL, Malinova L, et al. 1999. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol. Psychiatry 45:1178-89
105. 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. USA 96:1698-703
106. Kaufmann WA, Humpel C, Alheid GF, Marksteiner J. 2003. Compartmentation of alpha 1 and alpha 2 GABA(A) receptor subunits within rat extended amygdala: implications for benzodiazepine action. Brain Res. 964:91-99
107. Kendler KS. 2001. Twin studies of psychiatric illness: an update. Arch. Gen. Psychiatry 58:1005-14
108. Kessler RC, Greenberg PE. 2002. The economic burden of anxiety and stress disorders. See Davis et al. 2002, pp. 981-92
109. Kishimoto T, Radulovic J, Radulovic M, Lin CR, Schrick C, et al. 2000. Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat. Genet. 24:415-19
110. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, et al. 1998. Results of a genome-wide genetic screen for panic disorder. Am. J. Med. Genet. 81:139-47
111. Konig M, Zimmer AM, Steiner H, Holmes PV, Crawley JN, et al. 1996. Pain responses, anxiety and aggression in mice deficient in preproenkephalin. Nature 383:535-38
112. Kustova Y, Sei Y, Morse HC Jr, Basile AS. 1998. The influence of a targeted deletion of the ifngamma gene on emotional behaviors. Brain. Behav. Immun. 12:308-24
113. Landgraf R, Wigger A. 2002. High vs low anxiety-related behavior rats: an animal model of extremes in trait anxiety. Behav. Genet. 32:301-14
114. LeDoux JE. 2000. Emotion circuits in the brain. Annu. Rev. Neurosci. 23:155-84
115. Le Fur G, Guilloux F, Mitrani N, Mizoule J, Uzan A. 1979. Relationships between plasma corticosteroids and benzodiazepines in stress. J. Pharmacol. Exp. Ther. 211:305-8
116. Lesch KP. 2001a. Molecular foundation of anxiety disorders. J. Neural Transm. 108:717-46
117. Lesch KP. 2001b. Mouse anxiety: the power of knockout. Pharmacogenomics J. 1:187-92
118. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, et al. 1996. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527-31
119. Lesch KP, Meyer J, Glatz K, Flugge G, Hinney A, et al. 1997. The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication. J. Neural Transm. 104:1259-66
120. Li XB, Inoue T, Hashimoto S, Koyama T. 2001. Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear. Eur. J. Pharmacol. 425:43-50
121. Li YW, Hill G, Wong H, Kelly N, Ward K, et al. 2003. Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy. J. Pharmacol. Exp. Ther. 305:86-96
122. Liebsch G, Linthorst AC, Neumann ID, Reul JM, Holsboer F, Landgraf R. 1998a. 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 19:381-96
123. Liebsch G, Montkowski A, Holsboer F, Landgraf R. 1998b. Behavioural profiles of two wistar rat lines selectively bred for high or low anxiety-related behaviour. Behav. Brain Res. 94:301-10
124. Lister RG. 1987. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl.) 92:180-85
125. Liu D, Diorio J, Day JC, Francis DD, Meaney MJ. 2000. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat. Neurosci. 3:799-806
126. Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, et al. 1997. Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277:1659-62
127. Logue MW, Vieland VJ, Goedken RJ, Crowe RR. 2003. Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7. Am. J. Med. Genet. 121B:95-99
128. Low K, Crestani F, Keist R, Benke D, Brunig I, et al. 2000. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131-34
129. Lyons MJ, Goldberg J, Eisen SA, True W, Tsuang MT, et al. 1993. Do genes influence exposure to trauma? A twin study of combat. Am. J. Med. Genet. 48:22-27
130. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. 2000. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20:9104-10
131. Martins AP, Marras RA, Guimaraes FS. 1997. Anxiogenic effect of corticotropin-releasing hormone in the dorsal periaqueductal grey. Neuroreport 8:3601-4
132. Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, et al. 1996. Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev. Neurosci. 18:49-72
133. Melchior CL, Ritzmann RF. 1994. Dehydroepiandrosterone is an anxiolytic in mice on the plus maze. Pharmacol. Biochem. Behav. 47:437-41
134. Merali Z, Levac C, Anisman H. 2003. Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice. Biol. Psychiatry 54:552-65
135. Merikangas KR, Pine D. 2002. Genetic and other vulnerability factors for anxiety and stress disorders. See Davis et al. 2002, pp. 867-82
136. Miller DB, O'Callaghan JP. 2002. Neuroendocrine aspects of the response to stress. Metabolism 51:5-10
137. Mohler H, Crestani F, Rudolph U. 2001. GABA(A)-receptor subtypes: a new pharmacology. Curr. Opin. Pharmacol. 1:22-25
138. Mohler H, Fritschy JM, Rudolph U. 2002. A new benzodiazepine pharmacology. J. Pharmacol. Exp. Ther. 300:2-8
139. Morgan CA 3rd, Grillon C, Southwick SM, Davis M, Charney DS. 1995. Fear-potentiated startle in posttraumatic stress disorder. Biol. Psychiatry 38:378-85
140. Müller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, et al. 2003. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat. Neurosci. 6:1100-7
141. Mundo E, Richter MA, Sam F, Macciardi F, Kennedy JL. 2000. Is the 5-ht(1dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder? Am. J. Psychiatry 157:1160-61
142. Nie T, Abel T. 2001. Fear conditioning in inbred mouse strains: an analysis of the time course of memory. Behav. Neurosci. 115:951-56
143. Noyes R Jr, Clarkson C, Crowe RR, Yates WR, McChesney CM. 1987. A family study of generalized anxiety disorder. Am. J. Psychiatry 144:1019-24
144. Nusser Z, Sieghart W, Benke D, Fritschy JM, Somogyi P. 1996. Differential synaptic localization of two major gamma-aminobutyric acid type A receptor alpha subunits on hippocampal pyramidal cells. Proc. Natl. Acad. Sci. USA 93:11939-44
145. Ohara K, Nagai M, Suzuki Y, Ochiai M. 1998. No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res. 80:145-48
146. Ohl F, Toschi N, Wigger A, Henniger MS, Landgraf R. 2001. Dimensions of emotionality in a rat model of innate anxiety. Behav. Neurosci. 115:429-36
147. Oshima A, Flachskamm C, Reul JM, Holsboer F, Linthorst AC. 2003. Altered serotonergic neurotransmission but normal hypothalamic-pituitary-adrenocortical axis activity in mice chronically treated with the corticotropin-releasing hormone receptor type 1 antagonist NBI 30775. Neuropsychopharmacology 28:2148-59
148. Pape HC, Stork O. 2003. Genes and mechanisms in the amygdala involved in the formation of fear memory. Ann. NY Acad. Sci. 985:92-105
149. 1A receptor. Proc. Natl. Acad. Sci. USA 95:10734-39
150. 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 (Berl.) 154:336-42
151. 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 14:149-67
152. Pellow S, File SE. 1986. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol. Biochem. Behav. 24:525-29
153. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. 2000. GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101:815-50
154. Pletnikov MV, Storozheva ZI, Sherstnev VV. 1996. Relationship between memory and fear: developmental and pharmacological studies. Pharmacol. Biochem. Behav. 54:93-98
155. Plomin R, McClearn GE, Gora-Maslak G, Neiderhiser JM. 1991. Use of recombinant inbred strains to detect quantitative trait loci associated with behavior. Behav. Genet. 21:99-116
156. Quartermain D, Clemente J, Shemer A. 1993. 5-HT1A agonists disrupt memory of fear conditioning in mice. Biol. Psychiatry 33:247-54
157. Raber J, Akana SF, Bhatnagar S, Dallman MF, Wong D, Mucke L. 2000. Hypothalamic-pituitary-adrenal dysfunction in APOE (-/-) mice: possible role in behavioral and metabolic alterations. J. Neurosci. 20:2064-71
158. Radcliffe RA, Lowe MV, Wehner JM. 2000. Confirmation of contextual fear conditioning qtls by short-term selection. Behav. Genet. 30:183-91
159. Radley JJ, Jacobs BL. 2002. 5-HT1A receptor antagonist administration decreases cell proliferation in the dentate gyrus. Brain Res. 955:264-67
160. Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, et al. 1998. Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc. Natl. Acad. Sci. USA 95:14476-81
161. 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
162. Ramos A, Mellerin Y, Mormede P, Chaouloff F. 1998. A genetic and multifactorial analysis of anxiety-related behaviours in Lewis and SHR intercrosses. Behav. Brain Res. 96:195-205
163. Rex A, Sondern U, Voigt JP, Franck S, Fink H. 1996. Strain differences in fear-motivated behavior of rats. Pharmacol. Biochem. Behav. 54:107-11
164. Rodgers RJ, Dalvi A. 1997. Anxiety, defence and the elevated plus-maze. Neurosci. Biobehav. Rev. 21:801-10
165. Rodgers RJ, Johnson NJ. 1995. Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol. Biochem. Behav. 52:297-303
166. Roy-Byrne P, Afari N, Ashton S, Fischer M, Goldberg J, Buchwald D. 2002. Chronic fatigue and anxiety/depression: a twin study. Br. J. Psychiatry 180:29-34
167. Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, et al. 1999. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796-800
168. Saito N, Itouji A, Totani Y, Osawa I, Koide H, et al. 1993. Cellular and intracellular localization of epsilon-subspecies of protein kinase C in the rat brain; presynaptic localization of the epsilon-subspecies. Brain Res. 607:241-48
169. Santarelli L, Gobbi G, Debs PC, Sibille ET, Blier P, et al. 2001. Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc. Natl. Acad. Sci. USA 98:1912-17
170. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, et al. 2003. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805-9
171. Seymour PA, Schmidt AW, Schulz DW. 2003. The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a review. CNS Drug Rev. 9:57-96
172. Shephard RA, Broadhurst PL. 1982. Hyponeophagia and arousal in rats: effects of diazepam, 5-methoxy-N,N-dimethyltryptamine, d-amphetamine and food deprivation. Psychopharmacology (Berl.) 78:368-72
173. 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 (Berl.) 116:56-64
174. Skre I, Onstad S, Torgersen S, Philos DR, Lygren S, Kringlen E. 2000. The heritability of common phobic fear: a twin study of a clinical sample. J. Anxiety Disord. 14:549-62
175. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, et al. 1998. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093-102
176. Smoller JW, Acierno JS Jr, Rosenbaum JF, Biederman J, Pollack MH, et al. 2001a. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am. J. Med. Genet. 105:195-206
177. Smoller JW, Rosenbaum JF, Biederman J, Kennedy J, Dai D, et al. 2004. Association of a genetic marker at the corticotropin releasing hormone locus with behavioral inhibition. Biol. Psychiatry 54:1376-81
178. Smoller JW, Rosenbaum JF, Biederman J, Susswein LS, Kennedy J, et al. 2001b. Genetic association analysis of behavioral inhibition using candidate loci from mouse models. Am. J. Med. Genet. 105:226-35
179. Spivak B, Maayan R, Kotler M, Mester R, Gil-Ad I, et al. 2000. Elevated circulatory level of GABA(A)-antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol. Med. 30:1227-31
180. Stein MB, Jang KL, Taylor S, Vernon PA, Livesley WJ. 2002. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am. J. Psychiatry 159:1675-81
181. 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. 14:2579-84
182. Stork O, Welzl H, Wolfer D, Schuster T, Mantei N, et al. 2000. Recovery of emotional behaviour in neural cell adhesion molecule (NCAM) null mutant mice through transgenic expression of NCAM180. Eur. J. Neurosci. 12:3291-306
183. Stork O, Welzl H, Wotjak CT, Hoyer D, Delling M, et al. 1999. Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. J. Neurobiol. 40:343-55
184. Stork O, Yamanaka H, Stork S, Kume N, Obata K. 2003. Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice. Genes Brain Behav. 2:65-70
185. Suaudeau C, Rinaldi D, Lepicard E, Venault P, Crusio WE, et al. 2000. Divergent levels of anxiety in mice selected for differences in sensitivity to a convulsant agent. Physiol. Behav. 71:517-23
186. Sullivan GM, Coplan JD, Kent JM, Gorman JM. 1999. The noradrenergic system in pathological anxiety: a focus on panic with relevance to generalized anxiety and phobias. Biol. Psychiatry 46:1205-18
187. 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. 21:305-8
188. Tarantino LM, Gould TJ, Druhan JP, Bucan M. 2000. Behavior and mutagenesis screens: the importance of baseline analysis of inbred strains. Mamm. Genome 11:555-64
189. Thorgeirsson TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, et al. 2003. Anxiety with panic disorder linked to chromosome 9q in Iceland. Am. J. Hum. Genet. 72:1221-30
190. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, et al. 1998. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat. Genet. 19:162-66
191. Toth M. 2003. 5-HT(1A) receptor knockout mouse as a genetic model of anxiety. Eur. J. Pharmacol. 463:177-84
192. Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, et al. 1999. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23:99-103
193. True WR, Rice J, Eisen SA, Heath AC, Goldberg J, et al. 1993. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch. Gen. Psychiatry 50:257-64
194. Trullas R, Skolnick P. 1993. Differences in fear motivated behaviors among inbred mouse strains. Psychopharmacology (Berl.) 111:323-31
195. Turri MG, Datta SR, DeFries J, Henderson ND, Flint J. 2001a. QTL analysis identifies multiple behavioral dimensions in ethological tests of anxiety in laboratory mice. Curr. Biol. 11:725-34
196. Turri MG, Henderson ND, DeFries JC, Flint J. 2001b. Quantitative trait locus mapping in laboratory mice derived from a replicated selection experiment for open-field activity. Genetics 158:1217-26
197. Vaillend C, Ungerer A. 1999. Behavioral characterization of mdx3cv mice deficient in C-terminal dystrophins. Neuromuscul. Disord. 9:296-304
198. Vallee M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S. 1997. Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J. Neurosci. 17:2626-36
199. van den Heuvel OA, van de Wetering BJ, Veltman DJ, Pauls DL. 2000. Genetic studies of panic disorder: a review. J. Clin. Psychiatry 61:756-66
200. van Gaalen MM, Steckler T. 2000. Behavioural analysis of four mouse strains in an anxiety test battery. Behav. Brain Res. 115:95-106
201. van Gaalen MM, Stenzel-Poore MP, Holsboer F, Steckler T. 2002. Effects of transgenic overproduction of CRH on anxiety-like behaviour. Eur. J. Neurosci. 15:2007-15
202. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, et al. 1995. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378:287-92
203. Vetter DE, Li C, Zhao L, Contarino A, Liberman MC, et al. 2002. Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior. Nat. Genet. 31:363-69
204. Wang X, Su H, Copenhagen LD, Vaishnav S, Pieri F, et al. 2002. Urocortin-deficient mice display normal stress-induced anxiety behavior and autonomic control but an impaired acoustic startle response. Mol. Cell. Biol. 22:6605-10
205. Wehner JM, Radcliffe RA, Rosmann ST, Christensen SC, Rasmussen DL, et al. 1997. Quantitative trait locus analysis of contextual fear conditioning in mice. Nat. Genet. 17:331-34
206. Wei F, Qiu CS, Liauw J, Robinson DA, Ho N, et al. 2002. Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat. Neurosci. 5:573-79
207. Weissman MM. 1993. Family genetic studies of panic disorder. J. Psychiatr. Res. 27(Suppl. 1):69-78
208. Weissman MM, Fyer AJ, Haghighi F, Heiman G, Deng Z, et al. 2000. Potential panic disorder syndrome: clinical and genetic linkage evidence. Am. J. Med. Genet. 96:24-35
209. A receptors is essential for benzodiazepine agonist binding. J. Biol. Chem. 267:1426-29
210. Wigger A, Loerscher P, Weissenbacher P, Holsboer F, Landgraf R. 2001. Cross-fostering and cross-breeding of HAB and LAB rats: a genetic rat model of anxiety. Behav. Genet. 31:371-82
211. Wood SJ, Toth M. 2001. Molecular pathways of anxiety revealed by knockout mice. Mol. Neurobiol. 23:101-19
212. Yedovitzky M, Mochly-Rosen D, Johnson JA, Gray MO, Ron D, et al. 1997. Translocation inhibitors define specificity of protein kinase C isoenzymes in pancreatic beta-cells. J. Biol. Chem. 272:1417-20
213. Yoshikawa T, Watanabe A, Ishitsuka Y, Nakaya A, Nakatani N. 2002. Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice. Genome Res. 12:357-66