The role of the serotonergic and GABA system in translational approaches in drug discovery for anxiety disorders

Frontiers in Pharmacology

Volumn 4 JUN, Issue , 2013, Pages

  Olivier, Jocelien D A ^a,b   Vinkers, Christiaan H ^c,d   Olivier, Berend ^c,e  

^a UPPSALA UNIVERSITY   (Sweden)

^b KAROLINSKA INSTITUTE   (Sweden)

^c UTRECHT UNIVERSITY   (Netherlands)

^d UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^e YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

5 ht; 5 HT2 receptor; 5 HT1A receptor; 5 HTT; 5 HTTLPR; Animal model; Gabaa; Translational

Indexed keywords

(3 CHLOROPHENYL)PIPERAZINE; 4 AMINOBUTYRIC ACID; 6 CHLORO 5 METHYL 1 [[2 [(2 METHYL 3 PYRIDYL)OXY] 5 PYRIDYL]CARBAMOYL]INDOLINE; AGOMELATINE; ANTIDEPRESSANT AGENT; AUTORECEPTOR; BRAIN DERIVED NEUROTROPHIC FACTOR; CORTICOTROPIN RELEASING FACTOR; DERAMCICLANE; DOPAMINE; EXCITATORY AMINO ACID TRANSPORTER 3; FLESINOXAN; GEPIRONE; GLUTAMIC ACID; IPSAPIRONE; KETANSERIN; NEUROPEPTIDE Y; NEUROTRANSMITTER; NORADRENALIN; PLACEBO; RGS2 PROTEIN; SEROTONIN; SEROTONIN 1A AGONIST; SEROTONIN 1A RECEPTOR; SEROTONIN TRANSPORTER; SEROTONIN UPTAKE INHIBITOR; TANDOSPIRONE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR PET1; UNCLASSIFIED DRUG; UNINDEXED DRUG;

5 HTT GENE; 5 HTTPR GENE; 5 HTTPRL GENE; ALLELE; ANXIETY DISORDER; CHROMOSOME 4; CLINICAL TRIAL (TOPIC); COPY NUMBER VARIATION; DRUG PROTEIN BINDING; DRUG RESEARCH; ENDOPHENOTYPE; ENVIRONMENTAL FACTOR; GABAERGIC SYSTEM; GENE; GENETIC ASSOCIATION; GENETIC IDENTIFICATION; GENETIC LINKAGE; GENETIC RISK; GENETIC VARIABILITY; HERITABILITY; HETEROZYGOSITY; HUMAN; NEUROPATHOLOGY; NONHUMAN; PATHOGENESIS; PERIAQUEDUCTAL GRAY MATTER; PROTEIN TARGETING; REVIEW; RNA TRANSLATION; SEROTONINERGIC SYSTEM; SINGLE NUCLEOTIDE POLYMORPHISM; SLC1A1 GENE; SLC6A4 GENE; TRANQUILIZING ACTIVITY; TREATMENT FAILURE; TREATMENT RESPONSE;

EID: 84881579420     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2013.00074     Document Type: Review

References (243)

1. Adamec, R., Burton, P., Blundell, J., Murphy, D. L., and Holmes, A. (2006). Vulnerability to mild predator stress in serotonin transporter knockout mice. Behav. Brain Res. 170, 126-140. doi: 10.1016/j.bbr.2006.02.012.
2. Akimova, E., Lanzenberger, R., and Kasper, S. (2009). The serotonin-1A receptor in anxiety disorders. Biol. Psychiatry 66, 627-635. doi: 10.1016/j.biopsych.2009.03.012.
3. Andrade, R., and Haj-Dahmane, S. (2013). Serotonin neuron diversity in the dorsal raphe. ACS Chem. Neurosci. 4, 22-25. doi: 10.1021/cn300224n.
4. Atack, J. R. (2010). GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics. Curr. Top. Behav. Neurosci. 2, 331-360. doi: 10.1007/7854_2009_30.
5. Atack, J. R., Wafford, K. A., Street, L. J., Dawson, G. R., Tye, S., Van Laere, K., et al. (2011). MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans. J. Psychopharmacol. 25, 314-328. doi: 10.1177/0269881109354927.
6. Atack, J. R., Wafford, K. A., Tye, S. J., Cook, S. M., Sohal, B., Pike, A., et al. (2006). TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J. Pharmacol. Exp. Ther. 316, 410-422. doi: 10.1124/jpet.105.089920.
7. Attar-Levy, D., Martinot, J. L., Blin, J., Dao-Castellana, M. H., Crouzel, C., Mazoyer, B., et al. (1999). The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol. Psychiatry 45, 180-186. doi: 10.1016/S0006-3223(98)00007-9.
8. Bagdy, E., Kiraly, I., and Harsing, L. G. Jr. (2000). Reciprocal innervation between serotonergic and GABAergic neurons in raphe nuclei of the rat. Neurochem. Res. 25, 1465-1473. doi: 10.1023/A:1007672008297.
9. Bagdy, G., Graf, M., Anheuer, Z. E., Modos, E. A., and Kantor, S. (2001). Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635. Int. J. Neuropsychopharmacol. 4, 399-408. doi: 10.1017/S1461145701002632.
10. Bar-Haim, Y., Lamy, D., Pergamin, L., Bakermans-Kranenburg, M. J., and van Ijzendoorn, M. H. (2007). Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychol. Bull. 133, 1-24. doi: 10.1037/0033-2909.133.1.1.
11. Bartolomucci, A., Carola, V., Pascucci, T., Puglisi-Allegra, S., Cabib, S., Lesch, K. P., et al. (2010). Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice. Dis. Model. Mech. 3, 459-470. doi: 10.1242/dmm.004614.
12. Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., and Williams, R. (2009). Vulnerability genes or plasticity genes? Mol. Psychiatry 14, 746-754. doi: 10.1038/mp.2009.44.
13. Benekareddy, M., Vadodaria, K. C., Nair, A. R., and Vaidya, V. A. (2011). Postnatal serotonin type 2 receptor blockade prevents the emergence of anxiety behavior, dysregulated stress-induced immediate early gene responses, and specific transcriptional changes that arise following early life stress. Biol. Psychiatry 70, 1024-1032. doi: 10.1016/j.biopsych.2011.08.005.
14. Bengel, D., Greenberg, B. D., Cora-Locatelli, G., Altemus, M., Heils, A., Li, Q., et al. (1999). Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Mol. Psychiatry 4, 463-466. doi: 10.1038/sj.mp.4000550.
15. Bengel, D., Murphy, D. L., Andrews, A. M., Wichems, C. H., Feltner, D., Heils, A., et al. (1998). Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice. Mol. Pharmacol. 53, 649-655.
16. Blanchard, R. J., and Blanchard, D. C. (1971). Defensive reactions in the albino rat. Learn. Motiv. 21, 351-362. doi: 10.1016/0023-9690(71)90016-6.
17. Blier, P., Pineyro, G., El, M. M., Bergeron, R., and de Montigny, C. (1998). Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotransmission. Ann. N. Y. Acad. Sci. 861, 204-216. doi: 10.1111/j.1749-6632.1998.tb10192.x.
18. Boissier, J. R., Simon, P., and Aron, C. (1968). A new method for rapid screening of minor tranquillizers in mice. Eur. J. Pharmacol. 4, 145-151. doi: 10.1159/000135006.
19. Bortolozzi, A., Castane, A., Semakova, J., Santana, N., Alvarado, G., Cortes, R., et al. (2012). Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol. Psychiatry 17, 612-623. doi: 10.1038/mp.2011.92.
20. Bourin, M., and Hascoet, M. (2010). Implication of 5-HT2 receptor subtypes in the mechanism of action of the GABAergic compound etifoxine in the four-plate test in Swiss mice. Behav. Brain Res. 208, 352-358. doi: 10.1016/j.bbr.2009.11.046.
21. Bouwknecht, J. A., Olivier, B., and Paylor, R. E. (2007). The stress-induced hyperthermia paradigm as a physiological animal model for anxiety: a review of pharmacological and genetic studies in the mouse. Neurosci. Biobehav. Rev. 31, 41-59. doi: 10.1016/j.neubiorev.2006.02.002.
22. Brigman, J. L., Mathur, P., Harvey-White, J., Izquierdo, A., Saksida, L. M., Bussey, T. J., et al. (2010). Pharmacological or genetic inactivation of the serotonin transporter improves reversal learning in mice. Cereb. Cortex 20, 1955-1963. doi: 10.1093/cercor/bhp266.
23. Brown, J. S., Kalish, H. I., and Farber, I. E. (1951). Conditioned fear as revealed by magnitude of startle response to an auditory stimulus. J. Exp. Psychol. 41, 317-328. doi: 10.1037/h0060166.
24. Carola, V., Frazzetto, G., Pascucci, T., Audero, E., Puglisi-Allegra, S., Cabib, S., et al. (2008). Identifying molecular substrates in a mouse model of the serotonin transporter × environment risk factor for anxiety and depression. Biol. Psychiatry 63, 840-846. doi: 10.1016/j.biopsych.2007.08.013.
25. Carola, V., Pascucci, T., Puglisi-Allegra, S., Cabib, S., and Gross, C. (2011). Effect of the interaction between the serotonin transporter gene and maternal environment on developing mouse brain. Behav. Brain Res. 217, 188-194. doi: 10.1016/j.bbr.2010.10.020.
26. Caspi, A., Hariri, A. R., Holmes, A., Uher, R., and Moffitt, T. E. (2010). Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am. J. Psychiatry 167, 509-527. doi: 10.1176/appi.ajp.2010.09101452.
27. Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386-389. doi: 10.1126/science.1083968.
28. Chang, J. C., Tomlinson, I. D., Warnement, M. R., Ustione, A., Carneiro, A. M., Piston, D. W., et al. (2012). Single molecule analysis of serotonin transporter regulation using antagonist-conjugated quantum dots reveals restricted, p38 MAPK-dependent mobilization underlying uptake activation. J. Neurosci. 32, 8919-8929. doi: 10.1523/JNEUROSCI.0048-12.2012.
29. Chantarujikapong, S. I., Scherrer, J. F., Xian, H., Eisen, S. A., Lyons, M. J., Goldberg, J., et al. (2001). A twin study of generalized anxiety disorder symptoms, panic disorder symptoms and post-traumatic stress disorder in men. Psychiatry Res. 103, 133-145. doi: 10.1016/S0165-1781(01)00285-2.
30. Chase, T. N., Katz, R. I., and Kopin, I. J. (1970). Effect of diazepam on fate of intracisternally injected serotonin-C14. Neuropharmacology 9, 103-108. doi: 10.1016/0028-3908(70)90053-5.
31. Chen, G., Henter, I. D., and Manji, H. K. (2010). Translational research in bipolar disorder: emerging insights from genetically based models. Mol. Psychiatry 15, 883-895. doi: 10.1038/mp.2010.3.
32. Choi, W. S., Lee, B. H., Yang, J. C., and Kim, Y. K. (2010). Association study between 5-HT1A receptor gene C(-1019)G polymorphism and panic disorder in a Korean population. Psychiatry Investig. 7, 141-146. doi: 10.4306/pi.2010.7.2.141.
33. Christmas, D., Hood, S., and Nutt, D. (2008). Potential novel anxiolytic drugs. Curr. Pharm. Des 14, 3534-3546. doi: 10.2174/138161208786848775.
34. Cremers, T. I., Giorgetti, M., Bosker, F. J., Hogg, S., Arnt, J., Mork, A., et al. (2004). Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29, 1782-1789. doi: 10.1038/sj.npp.1300474.
35. Crow, T. J. (2011). The missing genes: what happened to the heritability of psychiatric disorders? Mol. Psychiatry 16, 362-364. doi: 10.1038/mp.2010.92.
36. Cryan, J. F., and Holmes, A. (2005). The ascent of mouse: advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4, 775-790. doi: 10.1038/nrd1825.
37. Cryan, J. F., and Sweeney, F. F. (2011). The age of anxiety: role of animal models of anxiolytic action in drug discovery. Br. J. Pharmacol. 164, 1129-1161. doi: 10.1111/j.1476-5381.2011.01362.x.
38. Czobor, P., Skolnick, P., Beer, B., and Lippa, A. (2010). A multicenter, placebo-controlled, double-blind, randomized study of efficacy and safety of ocinaplon (DOV 273,547) in generalized anxiety disorder. CNS Neurosci. Ther. 16, 63-75. doi: 10.1111/j.1755-5949.2009.00109.x.
39. Dawson, N., Ferrington, L., Lesch, K. P., and Kelly, P. A. (2011). Cerebral metabolic responses to 5-HT2A/C receptor activation in mice with genetically modified serotonin transporter (SERT) expression. Eur. Neuropsychopharmacol. 21, 117-128. doi: 10.1016/j.euroneuro.2010.10.006.
40. de Boer, S. F., and Koolhaas, J. M. (2003). Defensive burying in rodents: ethology, neurobiology and psychopharmacology. Eur. J. Pharmacol. 463, 145-161. doi: 10.1016/S0014-2999(03)01278-0.
41. Deckert, J., Catalano, M., Syagailo, Y. V., Bosi, M., Okladnova, O., Di, B. D., et al. (1999). Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum. Mol. Genet. 8, 621-624. doi: 10.1093/hmg/8.4.621.
42. Deckert, J., Nothen, M. M., Franke, P., Delmo, C., Fritze, J., Knapp, M., et al. (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. doi: 10.1038/sj.mp.4000345.
43. Dias, R., Sheppard, W. F., Fradley, R. L., Garrett, E. M., Stanley, J. L., Tye, S. J., et al. (2005). Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J. Neurosci. 25, 10682-10688. doi: 10.1523/JNEUROSCI.1166-05.2005.
44. Digangi, J., Guffanti, G., McLaughlin, K. A., and Koenen, K. C. (2013). Considering trauma exposure in the context of genetics studies of posttraumatic stress disorder: a systematic review. Biol. Mood Anxiety Disord. 3, 2. doi: 10.1186/2045-5380-3-2.
45. Domschke, K., Freitag, C. M., Kuhlenbaumer, G., Schirmacher, A., Sand, P., Nyhuis, P., et al. (2004). Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int. J. Neuropsychopharmacol. 7, 183-188. doi: 10.1017/S146114570400416X.
46. Drabant, E. M., Ramel, W., Edge, M. D., Hyde, L. W., Kuo, J. R., Goldin, P. R., et al. (2012). Neural mechanisms underlying 5-HTTLPR-related sensitivity to acute stress. Am. J. Psychiatry 169, 397-405. doi: 10.1176/appi.ajp.2011.10111699.
47. Drago, A., Ronchi, D. D., and Serretti, A. (2008). 5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Int. J. Neuropsychopharmacol. 11, 701-721. doi: 10.1017/S1461145707008218.
48. Eley, T. C., Hudson, J. L., Creswell, C., Tropeano, M., Lester, K. J., Cooper, P., et al. (2012). Therapygenetics: the 5HTTLPR and response to psychological therapy. Mol. Psychiatry 17, 236-237. doi: 10.1038/mp.2011.132.
49. Etkin, A., and Wager, T. D. (2007). Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476-1488. doi: 10.1176/appi.ajp.2007.07030504.
50. Fabre, V., Beaufour, C., Evrard, A., Rioux, A., Hanoun, N., Lesch, K. P., et al. (2000). Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur. J. Neurosci. 12, 2299-2310. doi: 10.1046/j.1460-9568.2000.00126.x.
51. Fakra, E., Hyde, L. W., Gorka, A., Fisher, P. M., Munoz, K. E., Kimak, M., et al. (2009). Effects of HTR1A C(-1019)G on amygdala reactivity and trait anxiety. Arch. Gen. Psychiatry 66, 33-40. doi: 10.1001/archpsyc.66.1.33.
52. Fernandez-Guasti, A., and Lopez-Rubalcava, C. (1998). Modification of the anxiolytic action of 5-HT1A compounds by GABA-benzodiazepine agents in rats. Pharmacol. Biochem. Behav. 60, 27-32. doi: 10.1016/S0091-3057(97)00482-6.
53. Fernando, A. B., and Robbins, T. W. (2011). Animal models of neuropsychiatric disorders. Annu. Rev. Clin. Psychol. 7, 39-61. doi: 10.1146/annurev-clinpsy-032210-104454.
54. Feusner, J., Ritchie, T., Lawford, B., Young, R. M., Kann, B., and Noble, E. P. (2001). GABA(A) receptor beta 3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population. Psychiatry Res. 104, 109-117. doi: 10.1016/S0165-1781(01)00296-7.
55. File, S. E., and Seth, P. (2003). A review of 25 years of the social interaction test. Eur. J. Pharmacol. 463, 35-53. doi: 10.1016/S0014-2999(03)01273-1.
56. Finger, E. C., Marsh, A. A., Buzas, B., Kamel, N., Rhodes, R., Vythilingham, M., et al. (2007). The impact of tryptophan depletion and 5-HTTLPR genotype on passive avoidance and response reversal instrumental learning tasks. Neuropsychopharmacology 32, 206-215. doi: 10.1038/sj.npp.1301182.
57. Flint, J., and Shifman, S. (2008). Animal models of psychiatric disease. Curr. Opin. Genet. Dev. 18, 235-240. doi: 10.1016/j.gde.2008.07.002.
58. Friedman, M. J., Resick, P. A., Bryant, R. A., Strain, J., Horowitz, M., and Spiegel, D. (2011). Classification of trauma and stressor-related disorders in DSM-5. Depress. Anxiety 28, 737-749. doi: 10.1002/da.20845.
59. Fyer, A. J., Hamilton, S. P., Durner, M., Haghighi, F., Heiman, G. A., Costa, R., et al. (2006). A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol. Psychiatry 60, 388-401. doi: 10.1016/j.biopsych.2006.04.018.
60. Gao, B., Fritschy, J. M., Benke, D., and Mohler, H. (1993). Neuron-specific expression of GABAA-receptor subtypes: differential association of the alpha 1- and alpha 3-subunits with serotonergic and GABAergic neurons. Neuroscience 54, 881-892. doi: 10.1016/0306-4522(93)90582-Z.
61. Gardier, A. M., Malagie, I., Trillat, A. C., Jacquot, C., and Artigas, F. (1996). Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies. Fundam. Clin. Pharmacol. 10, 16-27. doi: 10.1111/j.1472-8206.1996.tb00145.x.
62. Garner, M., Mohler, H., Stein, D. J., Mueggler, T., and Baldwin, D. S. (2009). Research in anxiety disorders: from the bench to the bedside. Eur. Neuropsychopharmacol. 19, 381-390. doi: 10.1016/j.euroneuro.2009.01.011.
63. Gaspar, P., and Lillesaar, C. (2012). Probing the diversity of serotonin neurons. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 2382-2394. doi: 10.1098/rstb.2011.0378.
64. Gelernter, J., Bonvicini, K., Page, G., Woods, S. W., Goddard, A. W., Kruger, S., et al. (2001). Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am. J. Med. Genet. 105, 548-557. doi: 10.1002/ajmg.1496.
65. Gelernter, J., Page, G. P., Bonvicini, K., Woods, S. W., Pauls, D. L., and Kruger, S. (2003). A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan. Mol. Psychiatry 8, 71-82. doi: 10.1038/sj.mp.4001224.
66. Gelernter, J., Page, G. P., Stein, M. B., and Woods, S. W. (2004). Genome-wide linkage scan for loci predisposing to social phobia: evidence for a chromosome 16 risk locus. Am. J. Psychiatry 161, 59-66. doi: 10.1176/appi.ajp.161.1.59.
67. Gershon, E. S., Alliey-Rodriguez, N., and Liu, C. (2011). After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. Am. J. Psychiatry 168, 253-256. doi: 10.1176/appi.ajp.2010.10091340.
68. Gervasoni, D., Peyron, C., Rampon, C., Barbagli, B., Chouvet, G., Urbain, N., et al. (2000). Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons. J. Neurosci. 20, 4217-4225.
69. Glenn, A. L. (2011). The other allele: exploring the long allele of the serotonin transporter gene as a potential risk factor for psychopathy: a review of the parallels in findings. Neurosci. Biobehav. Rev. 35, 612-620. doi: 10.1016/j.neubiorev.2010.07.005.
70. Gomes, K. S., and Nunes-de-Souza, R. L. (2009). Implication of the 5-HT2A and 5-HT2C (but not 5HT1A) receptors located within the periaqueductal gray in the elevated plus-maze test-retest paradigm in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 1261-1269. doi: 10.1016/j.pnpbp.2009.07.015.
71. Grabe, H. J., Schwahn, C., Appel, K., Mahler, J., Schulz, A., Spitzer, C., et al. (2011). Update on the 2005 paper: moderation of mental and physical distress by polymorphisms in the 5-HT transporter gene by interacting with social stressors and chronic disease burden. Mol. Psychiatry 16, 354-356. doi: 10.1038/mp.2010.45.
72. Gross, C., Zhuang, X., Stark, K., Ramboz, S., Oosting, R., Kirby, L., et al. (2002). Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396-400. doi: 10.1038/416396a.
73. Guilloux, J. P., David, D. J., Guiard, B. P., Chenu, F., Reperant, C., Toth, M., et al. (2006). Blockade of 5-HT1A receptors by (+/-)-pindolol potentiates cortical 5-HT outflow, but not antidepressant-like activity of paroxetine: microdialysis and behavioral approaches in 5-HT1A receptor knockout mice. Neuropsychopharmacology 31, 2162-2172.
74. Hamilton, S. P. (2009). Linkage and association studies of anxiety disorders. Depress. Anxiety 26, 976-983. doi: 10.1002/da.20615.
75. Hamilton, S. P., Fyer, A. J., Durner, M., Heiman, G. A., Baisre de Leon, A., Hodge, S. E., et al. (2003). Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc. Natl. Acad. Sci. U.S.A. 100, 2550-2555. doi: 10.1073/pnas.0335669100.
76. Hamilton, S. P., Slager, S. L., de Leon, A. B., Heiman, G. A., Klein, D. F., Hodge, S. E., et al. (2004). Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology 29, 558-565. doi: 10.1038/sj.npp.1300311.
77. Hamilton, S. P., Slager, S. L., Heiman, G. A., Deng, Z., Haghighi, F., Klein, D. 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. doi: 10.1016/S0006-3223(01)01322-1.
78. Hankin, B. L., Nederhof, E., Oppenheimer, C. W., Jenness, J., Young, J. F., Abela, J. R., et al. (2011). Differential susceptibility in youth: evidence that 5-HTTLPR x positive parenting is associated with positive affect 'for better and worse'. Transl. Psychiatry 1, e44. doi: 10.1038/tp.2011.44.
79. Harandi, M., Aguera, M., Gamrani, H., Didier, M., Maitre, M., Calas, A., et al. (1987). gamma-Aminobutyric acid and 5-hydroxytryptamine interrelationship in the rat nucleus raphe dorsalis: combination of radioautographic and immunocytochemical techniques at light and electron microscopy levels. Neuroscience 21, 237-251. doi: 10.1016/0306-4522(87)90336-8.
80. Hariri, A. R. (2009). The neurobiology of individual differences in complex behavioral traits. Annu. Rev. Neurosci. 32, 225-247. doi: 10.1146/annurev.neuro.051508.135335.
81. Hariri, A. R., and Holmes, A. (2006). Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn. Sci. 10, 182-191. doi: 10.1016/j.tics.2006.02.011.
82. Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400-403. doi: 10.1126/science.1071829.
83. Hattori, E., Ebihara, M., Yamada, K., Ohba, H., Shibuya, H., and 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. doi: 10.1038/sj.mp.4000875.
84. Heisler, L. K., Chu, H. M., Brennan, T. J., Danao, J. A., Bajwa, P., Parsons, L. H., et al. (1998). Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl. Acad. Sci. U.S.A. 95, 15049-15054. doi: 10.1073/pnas.95.25.15049.
85. Hettema, J. M., An, S. S., Neale, M. C., Bukszar, J., van den Oord, E. J., Kendler, K. S., et al. (2006). Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol. Psychiatry 11, 752-762. doi: 10.1038/sj.mp.4001845.
86. Hettema, J. M., Neale, M. C., and Kendler, K. S. (2001). A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am. J. Psychiatry 158, 1568-1578. doi: 10.1176/appi.ajp.158.10.1568.
87. Hettema, J. M., Prescott, C. A., Myers, J. M., Neale, M. C., and Kendler, K. S. (2005). The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch. Gen. Psychiatry 62, 182-189. doi: 10.1001/archpsyc.62.2.182.
88. Holmes, A. (2008). Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease. Neurosci. Biobehav. Rev. 32, 1293-1314. doi: 10.1016/j.neubiorev.2008.03.006.
89. Holmes, A., Yang, R. J., Murphy, D. L., and Crawley, J. N. (2002). Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 27, 914-923. doi: 10.1016/S0893-133X(02)00374-3.
90. Homberg, J. R., de Boer, S. F., Raaso, H. S., Olivier, J. D., Verheul, M., Ronken, E., et al. (2008a). Adaptations in pre- and postsynaptic 5-HT(1A) receptor function and cocaine supersensitivity in serotonin transporter knockout rats. Psychopharmacology (Berl.) 200, 367-380. doi: 10.1007/s00213-008-1212-x.
91. Homberg, J. R., van den Bos, R., den Heijer, E., Suer, R., and Cuppen, E. (2008b). Serotonin transporter dosage modulates long-term decision-making in rat and human. Neuropharmacology 55, 80-84. doi: 10.1016/j.neuropharm.2008.04.016.
92. Homberg, J. R., and Lesch, K. P. (2011). Looking on the bright side of serotonin transporter gene variation. Biol. Psychiatry 69, 513-519. doi: 10.1016/j.biopsych.2010.09.024.
93. Homberg, J. R., Olivier, J. D., Smits, B. M., Mul, J. D., Mudde, J., Verheul, M., et al. (2007a). Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system. Neuroscience 146, 1662-1676. doi: 10.1016/j.neuroscience.2007.03.030.
94. Homberg, J. R., Pattij, T., Janssen, M. C., Ronken, E., de Boer, S. F., Schoffelmeer, A. N., et al. (2007b). Serotonin transporter deficiency in rats improves inhibitory control but not behavioural flexibility. Eur. J. Neurosci. 26, 2066-2073. doi: 10.1111/j.1460-9568.2007.05839.x.
95. Homberg, J. R., Schubert, D., and Gaspar, P. (2010). New perspectives on the neurodevelopmental effects of SSRIs. Trends Pharmacol. Sci. 31, 60-65. doi: 10.1016/j.tips.2009.11.003.
96. Homberg, J. R., and van den Hove, D. L. (2012). The serotonin transporter gene and functional and pathological adaptation to environmental variation across the life span. Prog. Neurobiol. 99, 117-127. doi: 10.1016/j.pneurobio.2012.08.003.
97. Hovatta, I., and Barlow, C. (2008). Molecular genetics of anxiety in mice and men. Ann. Med. 40, 92-109. doi: 10.1080/07853890701747096.
98. Huot, R. L., Thrivikraman, K. V., Meaney, M. J., and Plotsky, P. M. (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, 366-373. doi: 10.1007/s002130100701.
99. Inada, Y., Yoneda, H., Koh, J., Sakai, J., Himei, A., Kinoshita, Y., et al. (2003). Positive association between panic disorder and polymorphism of the serotonin 2A receptor gene. Psychiatry Res. 118, 25-31. doi: 10.1016/S0165-1781(03)00064-7.
100. Jansen, F., Heiming, R. S., Lewejohann, L., Touma, C., Palme, R., Schmitt, A., et al. (2010). Modulation of behavioural profile and stress response by 5-HTT genotype and social experience in adulthood. Behav. Brain Res. 207, 21-29. doi: 10.1016/j.bbr.2009.09.033.
101. Jasinska, A. J., Lowry, C. A., and Burmeister, M. (2012). Serotonin transporter gene, stress and raphe-raphe interactions: a molecular mechanism of depression. Trends Neurosci. 35, 395-402. doi: 10.1016/j.tins.2012.01.001.
102. Jennings, K. A., Loder, M. K., Sheward, W. J., Pei, Q., Deacon, R. M., Benson, M. A., et al. (2006). Increased expression of the 5-HT transporter confers a low-anxiety phenotype linked to decreased 5-HT transmission. J. Neurosci. 26, 8955-8964. doi: 10.1523/JNEUROSCI.5356-05.2006.
103. Kaabi, B., Gelenter, J., Woods, S. W., Goddard, A., Page, G. P., and Elston, R. C. (2006). Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus. Am. J. Hum. Genet. 78, 543-553.
104. Kalin, N. H., Shelton, S. E., Fox, A. S., Rogers, J., Oakes, T. R., and Davidson, R. J. (2008). The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. Mol. Psychiatry 13, 1021-1027. doi: 10.1038/mp.2008.37.
105. Kalinichev, M., Easterling, K. W., Plotsky, P. M., and Holtzman, S. G. (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, 131-140. doi: 10.1016/S0091-3057(02)00781-5.
106. Kalueff, A. V., and Nutt, D. J. (2007). Role of GABA in anxiety and depression. Depress. Anxiety 24, 495-517. doi: 10.1002/da.20262.
107. Kalueff, A. V., Olivier, J. D., Nonkes, L. J., and Homberg, J. R. (2010). Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes. Neurosci. Biobehav. Rev. 34, 373-386. doi: 10.1016/j.neubiorev.2009.08.003.
108. Kas, M. J., Krishnan, V., Gould, T. D., Collier, D. A., Olivier, B., Lesch, K. P., et al. (2011). Advances in multidisciplinary and cross-species approaches to examine the neurobiology of psychiatric disorders. Eur. Neuropsychopharmacol. 21, 532-544. doi: 10.1016/j.euroneuro.2010.12.001.
109. Kennedy, J. L., Bradwejn, J., Koszycki, D., King, N., Crowe, R., Vincent, J., et al. (1999). Investigation of cholecystokinin system genes in panic disorder. Mol. Psychiatry 4, 284-285. doi: 10.1038/sj.mp.4000507.
110. Kiyasova, V., Bonnavion, P., Scotto-Lomassese, S., Fabre, V., Sahly, I., Tronche, F., et al. (2013). A subpopulation of serotonergic neurons that do not express the 5-HT1A autoreceptor. ACS Chem. Neurosci. 4, 89-95. doi: 10.1021/cn300157s.
111. Kiyasova, V., Fernandez, S. P., Laine, J., Stankovski, L., Muzerelle, A., Doly, S., et al. (2011). A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei. J. Neurosci. 31, 2756-2768. doi: 10.1523/JNEUROSCI.4080-10.2011.
112. Klein, C., Lohmann, K., and Ziegler, A. (2012). The promise and limitations of genome-wide association studies. JAMA. doi: 10.1001/2012.jama.10823 [Epub ahead of print].
113. Knowles, J. A., Fyer, A. J., Vieland, V. J., Weissman, M. M., Hodge, S. E., Heiman, G. A., et al. (1998). Results of a genome-wide genetic screen for panic disorder. Am. J. Med. Genet. 81, 139-147. doi: 10.1002/(SICI)1096-8628(19980328)81:2<139::AID-AJMG4>3.0.CO;2-R.
114. Knutsen, L. J. (2011). Drug discovery management, small is still beautiful: why a number of companies get it wrong. Drug Discov. Today 16, 476-484. doi: 10.1016/j.drudis.2011.04.002.
115. Kusserow, H., Davies, B., Hortnagl, H., Voigt, I., Stroh, T., Bert, B., et al. (2004). Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors. Brain Res. Mol. Brain Res. 129, 104-116. doi: 10.1016/j.molbrainres.2004.06.028.
116. Lanfumey, L., Mongeau, R., Cohen-Salmon, C., and Hamon, M. (2008). Corticosteroid-serotonin interactions in the neurobiological mechanisms of stress-related disorders. Neurosci. Biobehav. Rev. 32, 1174-1184. doi: 10.1016/j.neubiorev.2008.04.006.
117. Lee, H. J., Lee, M. S., Kang, R. H., Kim, H., Kim, S. D., Kee, B. S., et al. (2005). Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depress. Anxiety 21, 135-139. doi: 10.1002/da.20064.
118. Le François, B., Czesak, M., Steubl, D., and Albert, P. R. (2008). Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology 55, 977-985. doi: 10.1016/j.neuropharm.2008.06.046.
119. Lesch, K. P. (2001). Molecular foundation of anxiety disorders. J. Neural. Transm. 108, 717-746. doi: 10.1007/s007020170048.
120. Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527-1531. doi: 10.1126/science.274.5292.1527.
121. Lesch, K. P., and Gutknecht, L. (2004). Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics. Int. J. Neuropsychopharmacol. 7, 381-385. doi: 10.1017/S1461145704004845.
122. Leysen, J. E. (2004). 5-HT2 receptors. Curr. Drug Targets CNS Neurol. Disord. 3, 11-26. doi: 10.2174/1568007043482598.
123. Line, S. J., Barkus, C., Coyle, C., Jennings, K. A., Deacon, R. M., Lesch, K. P., et al. (2011). Opposing alterations in anxiety and species-typical behaviours in serotonin transporter overexpressor and knockout mice. Eur. Neuropsychopharmacol. 21, 108-116. doi: 10.1016/j.euroneuro.2010.08.005.
124. Lippa, A., Czobor, P., Stark, J., Beer, B., Kostakis, E., Gravielle, M., et al. (2005). Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator. Proc. Natl. Acad. Sci. U.S.A. 102, 7380-7385. doi: 10.1073/pnas.0502579102.
125. Lista, A., Blier, P., and de Montigny, C. (1989). In vivo presynaptic modulation of serotonergic neurotransmission in the rat hippocampus by diazepam. Eur. J. Pharmacol. 171, 229-231. doi: 10.1016/0014-2999(89)90111-8.
126. Logue, M. W., Baldwin, C., Guffanti, G., Melista, E., Wolf, E. J., Reardon, A. F., et al. (2012). A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Mol. Psychiatry. doi: 10.1038/mp.2012.113 [Epub ahead of print].
127. 2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice. J. Neurosci. 28, 6250-6257. doi: 10.1523/JNEUROSCI.5219-07.2008.
128. Lubke, G. H., Hottenga, J. J., Walters, R., Laurin, C., de Geus, E. J., Willemsen, G., et al. (2012). Estimating the genetic variance of major depressive disorder due to all single nucleotide polymorphisms. Biol. Psychiatry 72, 707-709. doi: 10.1016/j.biopsych.2012.03.011.
129. Magalhaes, A. C., Holmes, K. D., Dale, L. B., Comps-Agrar, L., Lee, D., Yadav, P. N., et al. (2010). CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling. Nat. Neurosci. 13, 622-629. doi: 10.1038/nn.2529.
130. Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., et al. (2009). Finding the missing heritability of complex diseases. Nature 461, 747-753. doi: 10.1038/nature08494.
131. Maron, E., Nikopensius, T., Koks, S., Altmae, S., Heinaste, E., Vabrit, K., et al. (2005). Association study of 90 candidate gene polymorphisms in panic disorder. Psychiatr. Genet. 15, 17-24. doi: 10.1097/00041444-200503000-00004.
132. Maron, E., Tasa, G., Toru, I., Lang, A., Vasar, V., and Shlik, J. (2004). Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers. World J. Biol. Psychiatry 5, 149-154. doi: 10.1080/15622970410029927.
133. Martin, C. B., Ramond, F., Farrington, D. T., Aguiar, A. S. Jr., Chevarin, C., Berthiau, A. S., et al. (2013). RNA splicing and editing modulation of 5-HT2C receptor function: relevance to anxiety and aggression in VGV mice. Mol. Psychiatry 18, 656-665. doi: 10.1038/mp.2012.171.
134. Mathews, A., and MacLeod, C. (2005). Cognitive vulnerability to emotional disorders. Annu. Rev. Clin. Psychol. 1, 167-195. doi: 10.1146/annurev.clinpsy.1.102803.143916.
135. Mathews, T. A., Fedele, D. E., Coppelli, F. M., Avila, A. M., Murphy, D. L., and Andrews, A. M. (2004). Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J. Neurosci. Methods 140, 169-181. doi: 10.1016/j.jneumeth.2004.05.017.
136. McDougle, C. J., Epperson, C. N., Price, L. H., and Gelernter, J. (1998). Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol. Psychiatry 3, 270-273. doi: 10.1038/sj.mp.4000391.
137. McKernan, R. M., Rosahl, T. W., Reynolds, D. S., Sur, C., Wafford, K. A., Atack, J. R., et al. (2000). Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat. Neurosci. 3, 587-592. doi: 10.1038/75761.
138. Meneses, A. (2007a). Do serotonin(1-7) receptors modulate short and long-term memory? Neurobiol. Learn. Mem. 87, 561-572. doi: 10.1016/j.nlm.2006.12.005.
139. Meneses, A. (2007b). Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory. Behav. Brain Res. 184, 81-90. doi: 10.1016/j.bbr.2007.06.026.
140. Millan, M. J., Brocco, M., Gobert, A., and Dekeyne, A. (2005). Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl.) 177, 448-458. doi: 10.1007/s00213-004-1962-z.
141. Mirza, N. R., and Munro, G. (2010). The role of GABA(A) receptor subtypes as analgesic targets. Drug News Perspect. 23, 351-360. doi: 10.1358/dnp.2010.23.6.1489909.
142. Möhler, H. (2006). GABAA receptors in central nervous system disease: anxiety, epilepsy, and insomnia. J. Recept. Signal Transduct. Res. 26, 731-740. doi: 10.1080/10799890600920035.
143. Möhler, H., and Okada, T. (1977). Benzodiazepine receptor: demonstration in the central nervous system. Science 198, 849-851. doi: 10.1126/science.918669.
144. Montag, C., Fiebach, C. J., Kirsch, P., and Reuter, M. (2011). Interaction of 5-HTTLPR and a variation on the oxytocin receptor gene influences negative emotionality. Biol. Psychiatry 69, 601-603. doi: 10.1016/j.biopsych.2010.10.026.
145. Moya, P. R., Fox, M. A., Jensen, C. L., LaPorte, J. L., French, H. T., Wendland, J. R., et al. (2011). Altered 5-HT2C receptor agonist-induced responses and 5-HT2C receptor RNA editing in the amygdala of serotonin transporter knockout mice. BMC Pharmacol. 11:3. doi: 10.1186/1471-2210-11-3.
146. Muglia, P. (2011). From genes to therapeutic targets for psychiatric disorders - what to expect? Curr. Opin. Pharmacol. 11, 563-571. doi: 10.1016/j.coph.2011.08.003.
147. Muller, J. M., Morelli, E., Ansorge, M., and Gingrich, J. A. (2011). Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks. Genes Brain Behav. 10, 166-175. doi: 10.1111/j.1601-183X.2010.00652.x.
148. Munafo, M. R., Clark, T., and Flint, J. (2005). Does measurement instrument moderate the association between the serotonin transporter gene and anxiety-related personality traits? A meta-analysis. Mol. Psychiatry 10, 415-419. doi: 10.1038/sj.mp.4001627.
149. Munafo, M. R., Clark, T. G., Moore, L. R., Payne, E., Walton, R., and Flint, J. (2003). Genetic polymorphisms and personality in healthy adults: a systematic review and meta-analysis. Mol. Psychiatry 8, 471-484. doi: 10.1038/sj.mp.4001326.
150. Murphy, D. L., and Lesch, K. P. (2008). Targeting the murine serotonin transporter: insights into human neurobiology. Nat. Rev. Neurosci. 9, 85-96. doi: 10.1038/nrn2284.
151. Murrough, J. W., and Charney, D. S. (2011). The serotonin transporter and emotionality: risk, resilience, and new therapeutic opportunities. Biol. Psychiatry 69, 510-512. doi: 10.1016/j.biopsych.2011.01.019.
152. Narayanan, V., Heiming, R. S., Jansen, F., Lesting, J., Sachser, N., Pape, H. C., et al. (2011). Social defeat: impact on fear extinction and amygdala-prefrontal cortical theta synchrony in 5-HTT deficient mice. PLoS ONE 6:e22600. doi: 10.1371/journal.pone.0022600.
153. Naukkarinen, H., Raassina, R., Penttinen, J., Ahokas, A., Jokinen, R., Koponen, H., et al. (2005). Deramciclane in the treatment of generalized anxiety disorder: a placebo-controlled, double-blind, dose-finding study. Eur. Neuropsychopharmacol. 15, 617-623. doi: 10.1016/j.euroneuro.2005.03.002.
154. Nelson, E. C., Agrawal, A., Pergadia, M. L., Lynskey, M. T., Todorov, A. A., Wang, J. C., et al. (2009). Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults. Mol. Psychiatry 14, 234-235. doi: 10.1038/mp.2008.81.
155. Nemeroff, C. B. (2003). The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol. Bull. 37, 133-146.
156. Nietzer, S. L., Bonn, M., Jansen, F., Heiming, R. S., Lewejohann, L., Sachser, N., et al. (2011). Serotonin transporter knockout and repeated social defeat stress: impact on neuronal morphology and plasticity in limbic brain areas. Behav. Brain Res. 220, 42-54. doi: 10.1016/j.bbr.2011.01.011.
157. Nonkes, L. J., de Pooter, M., and Homberg, J. R. (2012). Behavioural therapy based on distraction alleviates impaired fear extinction in male serotonin transporter knockout rats. J. Psychiatry Neurosci. 37, 224-230. doi: 10.1503/jpn.110116.
158. Nonkes, L. J., Maes, J. H., and Homberg, J. R. (2013). Improved cognitive flexibility in serotonin transporter knockout rats is unchanged following chronic cocaine self-administration. Addict. Biol. 18, 434-440. doi: 10.1111/j.1369-1600.2011.00351.x.
159. Nothdurfter, C., Baghai, T. C., Schule, C., and Rupprecht, R. (2012). Translocator protein (18 kDa) (TSPO) as a therapeutic target for anxiety and neurologic disorders. Eur. Arch. Psychiatry Clin. Neurosci. 262(Suppl. 2), S107-S112. doi: 10.1007/s00406-012-0352-5.
160. Nunes-de-Souza, V., Nunes-de-Souza, R. L., Rodgers, R. J., and Canto-de-Souza, A. (2008). 5-HT2 receptor activation in the midbrain periaqueductal grey (PAG) reduces anxiety-like behaviour in mice. Behav. Brain Res. 187, 72-79. doi: 10.1016/j.bbr.2007.08.030.
161. Ohara, K., Suzuki, Y., Ochiai, M., Tsukamoto, T., Tani, K., and Ohara, K. (1999). A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 55-65. doi: 10.1016/S0278-5846(98)00091-8.
162. Olivier, B., Pattij, T., Wood, S. J., Oosting, R., Sarnyai, Z., and Toth, M. (2001). The 5-HT(1A) receptor knockout mouse and anxiety. Behav. Pharmacol. 12, 439-450. doi: 10.1097/00008877-200111000-00004.
163. Olivier, B., Soudijn, W., and van Wijngaarden, I. (1999). The 5-HT1A receptor and its ligands: structure and function. Prog. Drug Res. 52, 103-165. doi: 10.1007/978-3-0348-8730-4_3.
164. Olivier, J. D., Van Der Hart, M. G., Van Swelm, R. P., Dederen, P. J., Homberg, J. R., Cremers, T., et al. (2008). A study in male and female 5-HT transporter knockout rats: an animal model for anxiety and depression disorders. Neuroscience 152, 573-584. doi: 10.1016/j.neuroscience.2007.12.032.
165. Otowa, T., Kawamura, Y., Nishida, N., Sugaya, N., Koike, A., Yoshida, E., et al. (2012). Meta-analysis of genome-wide association studies for panic disorder in the Japanese population. Transl. Psychiatry 2, e186. doi: 10.1038/tp.2012.89.
166. Parks, C. L., Robinson, P. S., Sibille, E., Shenk, T., and Toth, M. (1998). Increased anxiety of mice lacking the serotonin1A receptor. Proc. Natl. Acad. Sci. U.S.A. 95, 10734-10739. doi: 10.1073/pnas.95.18.10734.
167. Pattij, T., Groenink, L., Oosting, R. S., van der Gugten, J., Maes, R. A., and Olivier, B. (2002). GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knockout mice on a 129/Sv background. Eur. J. Pharmacol. 447, 67-74. doi: 10.1016/S0014-2999(02)01893-9.
168. Pattij, T., Hijzen, T. H., Groenink, L., Oosting, R. S., van der Gugten, J., Maes, R. A., et al. (2001). Stress-induced hyperthermia in the 5-HT(1A) receptor knockout mouse is normal. Biol. Psychiatry 49, 569-574. doi: 10.1016/S0006-3223(00)01022-2.
169. Pham, X., Sun, C., Chen, X., van den Oord, E. J., Neale, M. C., Kendler, K. S., et al. (2009). Association study between GABA receptor genes and anxiety spectrum disorders. Depress. Anxiety 26, 998-1003. doi: 10.1002/da.20628.
170. Pluess, M., Velders, F. P., Belsky, J., van Ijzendoorn, M. H., Bakermans-Kranenburg, M. J., Jaddoe, V. W., et al. (2011). Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality. Biol. Psychiatry 69, 520-525. doi: 10.1016/j.biopsych.2010.10.006.
171. Polanczyk, G., Caspi, A., Williams, B., Price, T. S., Danese, A., Sugden, K., et al. (2009). Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch. Gen. Psychiatry 66, 978-985. doi: 10.1001/archgenpsychiatry.2009.114.
172. Pratt, J., Jenner, P., Reynolds, E. H., and Marsden, C. D. (1979). Clonazepam induces decreased serotoninergic activity in the mouse brain. Neuropharmacology 18, 791-799. doi: 10.1016/0028-3908(79)90024-8.
173. Quesseveur, G., Nguyen, H. T., Gardier, A. M., and Guiard, B. P. (2012). 5-HT2 ligands in the treatment of anxiety and depression. Expert Opin. Investig. Drugs 21, 1701-1725. doi: 10.1517/13543784.2012.719872.
174. Ramboz, S., Oosting, R., Amara, D. A., Kung, H. F., Blier, P., Mendelsohn, M., et al. (1998). Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc. Natl. Acad. Sci. U.S.A. 95, 14476-14481. doi: 10.1073/pnas.95.24.14476.
175. Ressler, K. J., and Mayberg, H. S. (2007). Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat. Neurosci. 10, 1116-1124. doi: 10.1038/nn1944.
176. Richardson-Jones, J. W., Craige, C. P., Guiard, B. P., Stephen, A., Metzger, K. L., Kung, H. F., et al. (2010). 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65, 40-52. doi: 10.1016/j.neuron.2009.12.003.
177. Risch, N., Herrell, R., Lehner, T., Liang, K. Y., Eaves, L., Hoh, J., et al. (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301, 2462-2471. doi: 10.1001/jama.2009.878.
178. Rodgers, R. J., Cao, B. J., Dalvi, A., and Holmes, A. (1997). Animal models of anxiety: an ethological perspective. Braz. J. Med. Biol. Res. 30, 289-304. doi: 10.1590/S0100-879X1997000300002.
179. Roiser, J. P., Blackwell, A. D., Cools, R., Clark, L., Rubinsztein, D. C., Robbins, T. W., et al. (2006a). Serotonin transporter polymorphism mediates vulnerability to loss of incentive motivation following acute tryptophan depletion. Neuropsychopharmacology 31, 2264-2272. doi: 10.1038/sj.npp.1301084.
180. Roiser, J. P., Rogers, R. D., Cook, L. J., and Sahakian, B. J. (2006b). The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls. Psychopharmacology (Berl.) 188, 213-227. doi: 10.1007/s00213-006-0495-z.
181. Roiser, J. P., Muller, U., Clark, L., and Sahakian, B. J. (2007). The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention. Int. J. Neuropsychopharmacol. 10, 449-461. doi: 10.1017/S146114570600705X.
182. Rothe, C., Gutknecht, L., Freitag, C., Tauber, R., Mossner, R., Franke, P., et al. (2004). Association of a functional 1019C > G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia. Int. J. Neuropsychopharmacol. 7, 189-192. doi: 10.1017/S1461145703004061.
183. Rothe, C., Koszycki, D., Bradwejn, J., King, N., Deluca, V., Tharmalingam, S., et al. (2006). Association of the Val158Met catechol O-methyltransferase genetic polymorphism with panic disorder. Neuropsychopharmacology 31, 2237-2242.
184. Rowlett, J. K., Platt, D. M., Lelas, S., Atack, J. R., and Dawson, G. R. (2005). Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proc. Natl. Acad. Sci. U.S.A. 102, 915-920. doi: 10.1073/pnas.0405621102.
185. Rudolph, U., and Knoflach, F. (2011). Beyond classical benzodiazepines: novel therapeutic potential of GABA(A) receptor subtypes. Nat. Rev. Drug Discov. 10, 685-697. doi: 10.1038/nrd3502.
186. Samochowiec, J., Hajduk, A., Samochowiec, A., Horodnicki, J., Stepien, G., Grzywacz, A., et al. (2004). Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res. 128, 21-26. doi: 10.1016/j.psychres.2004.05.012.
187. Sanchez, C. (2003). Stress-induced vocalisation in adult animals. A valid model of anxiety? Eur. J. Pharmacol. 463, 133-143. doi: 10.1016/S0014-2999(03)01277-9.
188. Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., et al. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805-809. doi: 10.1126/science.1083328.
189. Savitz, J., Lucki, I., and Drevets, W. C. (2009). 5-HT(1A) receptor function in major depressive disorder. Prog. Neurobiol. 88, 17-31. doi: 10.1016/j.pneurobio.2009.01.009.
190. Scott-Stevens, P., Atack, J. R., Sohal, B., and Worboys, P. (2005). Rodent pharmacokinetics and receptor occupancy of the GABAA receptor subtype selective benzodiazepine site ligand L-838417. Biopharm. Drug Dispos. 26, 13-20. doi: 10.1002/bdd.423.
191. Seedat, S., Niehaus, D. J., and Stein, D. J. (2001). The role of genes and family in trauma exposure and posttraumatic stress disorder. Mol. Psychiatry 6, 360-362. doi: 10.1038/sj.mp.4000867.
192. Shen, H. W., Hagino, Y., Kobayashi, H., Shinohara-Tanaka, K., Ikeda, K., Yamamoto, H., et al. (2004). Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29, 1790-1799. doi: 10.1038/sj.npp.1300476.
193. Shephard, R. A., and Broadhurst, P. L. (1982). Hyponeophagia and arousal in rats: effects of diazepam, 5-methoxy-N,N-dimethyltryptamine, d-amphetamine and food deprivation. Psychopharmacology (Berl.) 78, 368-372. doi: 10.1007/BF00433744.
194. Shephard, R. A., Buxton, D. A., and Broadhurst, P. L. (1982). Drug interactions do not support reduction in serotonin turnover as the mechanism of action of benzodiazepines. Neuropharmacology 21, 1027-1032. doi: 10.1016/0028-3908(82)90117-4.
195. Shifman, S., Bhomra, A., Smiley, S., Wray, N. R., James, M. R., Martin, N. G., et al. (2008). A whole genome association study of neuroticism using DNA pooling. Mol. Psychiatry 13, 302-312. doi: 10.1038/sj.mp.4002048.
196. Sibille, E., Pavlides, C., Benke, D., and Toth, M. (2000). Genetic inactivation of the Serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J. Neurosci. 20, 2758-2765.
197. Smits, B. M., Mudde, J. B., van de Belt, J., Verheul, M., Olivier, J., Homberg, J., et al. (2006). Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis. Pharmacogenet. Genomics 16, 159-169.
198. Smoller, J. W., Acierno, J. S. Jr., Rosenbaum, J. F., Biederman, J., Pollack, M. H., Meminger, S., 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. doi: 10.1002/ajmg.1209.
199. Smoller, J. W., Rosenbaum, J. F., Biederman, J., Susswein, L. S., Kennedy, J., Kagan, J., et al. (2001b). Genetic association analysis of behavioral inhibition using candidate loci from mouse models. Am. J. Med. Genet. 105, 226-235. doi: 10.1002/ajmg.1328
200. Smoller, J. W., Block, S. R., and Young, M. M. (2009). Genetics of anxiety disorders: the complex road from DSM to DNA. Depress. Anxiety 26, 965-975. doi: 10.1002/da.20623.
201. Smoller, J. W., Gardner-Schuster, E., and Covino, J. (2008a). The genetic basis of panic and phobic anxiety disorders. Am. J. Med. Genet. C Semin. Med. Genet. 148C, 118-126. doi: 10.1002/ajmg.c.30174.
202. Smoller, J. W., Paulus, M. P., Fagerness, J. A., Purcell, S., Yamaki, L. H., Hirshfeld-Becker, D., et al. (2008b). Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch. Gen. Psychiatry 65, 298-308. doi: 10.1001/archgenpsychiatry.2007.48.
203. Sokolowska, E., and Hovatta, E. (2013). Anxiety genetics: findings from cross-species genome-wide approaches. Biol. Mood Anxiety Disord. 3, 9. doi: 10.1186/2045-5380-3-9.
204. Sora, I., Hall, F. S., Andrews, A. M., Itokawa, M., Li, X. F., Wei, H. B., et al. (2001). Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc. Natl. Acad. Sci. U.S.A. 98, 5300-5305. doi: 10.1073/pnas.091039298.
205. Sora, I., Wichems, C., Takahashi, N., Li, X. F., Zeng, Z., Revay, R., et al. (1998). Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc. Natl. Acad. Sci. U.S.A. 95, 7699-7704. doi: 10.1073/pnas.95.13.7699.
206. Stein, D. J., Ahokas, A. A., and de Bodinat, C. (2008). Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 28, 561-566. doi: 10.1097/JCP.0b013e318184ff5b.
207. Stein, L., Belluzzi, J. D., and Wise, C. D. (1977). Benzodiazepines: behavioral and neurochemical mechanisms. Am. J. Psychiatry 134, 665-669.
208. Stein, M. B., Campbell-Sills, L., and Gelernter, J. (2009). Genetic variation in 5HTTLPR is associated with emotional resilience. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 900-906. doi: 10.1002/ajmg.b.30916.
209. Steiner, J. A., Carneiro, A. M., and Blakely, R. D. (2008). Going with the flow: trafficking-dependent and -independent regulation of serotonin transport. Traffic 9, 1393-1402. doi: 10.1111/j.1600-0854.2008.00757.x.
210. Stollstorff, M., Bean, S. E., Anderson, L. M., Devaney, J. M., and Vaidya, C. J. (2013). Rationality and emotionality: serotonin transporter genotype influences reasoning bias. Soc. Cogn. Affect. Neurosci. 8, 404-409. doi: 10.1093/scan/nss011.
211. Sun, Y. V. (2012). Integration of biological networks and pathways with genetic association studies. Hum. Genet. 131, 1677-1686. doi: 10.1007/s00439-012-1198-7.
212. Taliani, S., Da Settimo, F., Da Pozzo, E., Chelli, B., and Martini, C. (2009). Translocator protein ligands as promising therapeutic tools for anxiety disorders. Curr. Med. Chem. 16, 3359-3380. doi: 10.2174/092986709789057653.
213. Tan, K. R., Brown, M., Labouebe, G., Yvon, C., Creton, C., Fritschy, J. M., et al. (2010). Neural bases for addictive properties of benzodiazepines. Nature 463, 769-774. doi: 10.1038/nature08758.
214. Tan, K. R., Rudolph, U., and Luscher, C. (2011). Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 34, 188-197. doi: 10.1016/j.tins.2011.01.004.
215. Thiebot, M. H. (1986). Are serotonergic neurons involved in the control of anxiety and in the anxiolytic activity of benzodiazepines? Pharmacol. Biochem. Behav. 24, 1471-1477. doi: 10.1016/0091-3057(86)90214-5.
216. Thiebot, M. H., Soubrie, P., Hamon, M., and Simon, P. (1984). Evidence against the involvement of serotonergic neurons in the anti-punishment activity of diazepam in the rat. Psychopharmacology (Berl.) 82, 355-359. doi: 10.1007/BF00427685.
217. Thoeringer, C. K., Binder, E. B., Salyakina, D., Erhardt, A., Ising, M., Unschuld, P. G., et al. (2007). Association of a Met88Val diazepam binding inhibitor (DBI) gene polymorphism and anxiety disorders with panic attacks. J. Psychiatr. Res. 41, 579-584. doi: 10.1016/j.jpsychires.2006.06.001.
218. Thoeringer, C. K., Ripke, S., Unschuld, P. G., Lucae, S., Ising, M., Bettecken, T., et al. (2009). The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders. J. Neural. Transm. 116, 649-657. doi: 10.1007/s00702-008-0075-y.
219. Thompson, B. J., Jessen, T., Henry, L. K., Field, J. R., Gamble, K. L., Gresch, P. J., et al. (2011). Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter. Proc. Natl. Acad. Sci. U.S.A. 108, 3785-3790. doi: 10.1073/pnas.1011920108.
220. Thorgeirsson, T. E., Oskarsson, H., Desnica, N., Kostic, J. P., Steffansson, J. G., Kolbeinsson, H., et al. (2003). Anxiety with panic disorder linked to chromosome 9q in Iceland. Am. J. Hum. Genet. 72, 1221-1230.
221. Tjurmina, O. A., Armando, I., Saavedra, J. M., Goldstein, D. S., and Murphy, D. L. (2002). Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology 143, 4520-4526. doi: 10.1210/en.2002-220416.
222. Trulson, M. E., Preussler, D. W., Howell, G. A., and Frederickson, C. J. (1982). Raphe unit activity in freely moving cats: effects of benzodiazepines. Neuropharmacology 21, 1045-1050. doi: 10.1016/0028-3908(82)90120-4.
223. Tye, K. M., and Deisseroth, K. (2012). Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat. Rev. Neurosci. 13, 251-266. doi: 10.1038/nrn3171.
224. van Bogaert, M. J., Oosting, R., Toth, M., Groenink, L., van Oorschot, R., and Olivier, B. (2006). Effects of genetic background and null mutation of 5-HT1A receptors on basal and stress-induced body temperature: modulation by serotonergic and GABAA-ergic drugs. Eur. J. Pharmacol. 550, 84-90. doi: 10.1016/j.ejphar.2006.08.058.
225. Van den Hove, D., Jakob, S. B., Schraut, K. G., Kenis, G., Schmitt, A., Kneitz, S., et al. (2011). Differential effects of prenatal stress in 5-Htt deficient mice: towards molecular mechanisms of gene × environment interactions. PLoS ONE 6:e22715. doi: 10.1371/journal.pone.0022715.
226. van Gestel, S., Forsgren, T., Claes, S., Del-Favero, J., Van Duijn, C. M., Sluijs, S., et al. (2002). Epistatic effect of genes from the dopamine and serotonin systems on the temperament traits of novelty seeking and harm avoidance. Mol. Psychiatry 7, 448-450. doi: 10.1038/sj.mp.4001005.
227. Varga, V., Szekely, A. D., Csillag, A., Sharp, T., and Hajos, M. (2001). Evidence for a role of GABA interneurones in the cortical modulation of midbrain 5-hydroxytryptamine neurones. Neuroscience 106, 783-792. doi: 10.1016/S0306-4522(01)00294-9.
228. Vinkers, C. H., Klanker, M., Groenink, L., Korte, S. M., Cook, J. M., Van Linn, M. L., et al. (2009). Dissociating anxiolytic and sedative effects of GABAAergic drugs using temperature and locomotor responses to acute stress. Psychopharmacology (Berl.) 204, 299-311. doi: 10.1007/s00213-009-1460-4.
229. Vinkers, C. H., Mirza, N. R., Olivier, B., and Kahn, R. S. (2010a). The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline. Expert Opin. Investig. Drugs 19, 1217-1233. doi: 10.1517/13543784.2010.513382.
230. Vinkers, C. H., van Oorschot, R., Korte, S. M., Olivier, B., and Groenink, L. (2010b). 5-HT1A receptor blockade reverses GABA(A) receptor alpha3 subunit-mediated anxiolytic effects on stress-induced hyperthermia. Psychopharmacology (Berl.) 211, 123-130. doi: 10.1007/s00213-010-1895-7.
231. Vinkers, C. H., van Oorschot, R., Nielsen, E. O., Cook, J. H., Hansen, H. H., Groenink, L., et al. (2012). GABA(A) receptor α subunits differentially contribute to diazepam tolerance after chronic treatment. PLoS ONE 7:e43054. doi: 10.1371/journal.pone.0043054.
232. Vogel, J. R., Beer, B., and Clody, D. E. (1971). A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21, 1-7. doi: 10.1007/BF00403989.
233. Walitza, S., Wendland, J. R., Gruenblatt, E., Warnke, A., Sontag, T. A., Tucha, O., et al. (2010). Genetics of early-onset obsessive-compulsive disorder. Eur. Child Adolesc. Psychiatry 19, 227-235. doi: 10.1007/s00787-010-0087-7.
234. Wang, Z., Valdes, J., Noyes, R., Zoega, T., and Crowe, R. R. (1998). Possible association of a cholecystokinin promotor polymorphism (CCK-36CT) with panic disorder. Am. J. Med. Genet. 81, 228-234. doi: 10.1002/(SICI)1096-8628(19980508)81:3<228::AID-AJMG5>3.0.CO;2-S.
235. Waters, A. M., Mogg, K., Bradley, B. P., and Pine, D. S. (2008). Attentional bias for emotional faces in children with generalized anxiety disorder. J. Am. Acad. Child Adolesc. Psychiatry 47, 435-442. doi: 10.1097/CHI.0b013e3181642992.
236. Weissman, M. M., Fyer, A. J., Haghighi, F., Heiman, G., Deng, Z., Hen, R., et al. (2000). Potential panic disorder syndrome: clinical and genetic linkage evidence. Am. J. Med. Genet. 96, 24-35. doi: 10.1002/(SICI)1096-8628(20000207)96:1<24::AID-AJMG7>3.0.CO;2-E.
237. Weisstaub, N. V., Zhou, M., Lira, A., Lambe, E., Gonzalez-Maeso, J., Hornung, J. P., et al. (2006). Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313, 536-540. doi: 10.1126/science.1123432.
238. Wellman, C. L., Izquierdo, A., Garrett, J. E., Martin, K. P., Carroll, J., Millstein, R., et al. (2007). Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J. Neurosci. 27, 684-691. doi: 10.1523/JNEUROSCI.4595-06.2007.
239. Wittchen, H. U. (2011). The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 21, 655-679. doi: 10.1016/j.euroneuro.2011.07.018.
240. Woo, J. M., Yoon, K. S., Choi, Y. H., Oh, K. S., Lee, Y. S., and Yu, B. H. (2004). The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J. Psychiatr. Res. 38, 365-370. doi: 10.1016/j.jpsychires.2004.01.001.
241. Wright, I. K., Upton, N., and Marsden, C. A. (1992). Effect of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze. Psychopharmacology (Berl.) 109, 338-346. doi: 10.1007/BF02245882.
242. Zanettini, C., Carola, V., Lo Lacono, L., Moles. A., Gross, C., and D'Amato, F. R. (2010). Postnatal handling reverses social anxiety in serotonin receptor 1A knockout mice. Genes Brain Behav. 9, 26-32. doi: 10.1111/j.1601-183X.2009.00531.x.
243. Zhang, G., Asgeirsdottir, H. N., Cohen, S. J., Munchow, A. H., Barrera, M. P., and Stackman, R. W. Jr. (2013). Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64, 403-413. doi: 10.1016/j.neuropharm.2012.06.007.