Table of Contents Author Guidelines Submit a Manuscript
Scientifica
Volume 2012, Article ID 821549, 16 pages
http://dx.doi.org/10.6064/2012/821549
Review Article

Serotonergic Modulation of Conditioned Fear

Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Radboud University Medical Centre, Geert Grooteplein 21, Route 126, 6525 EZ Nijmegen, The Netherlands

Received 23 August 2012; Accepted 26 September 2012

Academic Editors: R. C. Drugan, C. Marchand, P. Rada, and D. K. Ryugo

Copyright © 2012 Judith R. Homberg. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. L. M. Shin and I. Liberzon, “The neurocircuitry of fear, stress, and anxiety disorders,” Neuropsychopharmacology, vol. 35, no. 1, pp. 169–191, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. J. M. Zanoveli, M. C. Carvalho, J. M. Cunha, and M. L. Brandão, “Extracellular serotonin level in the basolateral nucleus of the amygdala and dorsal periaqueductal gray under unconditioned and conditioned fear states: an in vivo microdialysis study,” Brain Research, vol. 1294, pp. 106–115, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. M. Yokoyama, E. Suzuki, T. Sato, S. Maruta, S. Watanabe, and H. Miyaoka, “Amygdalic levels of dopamine and serotonin rise upon exposure to conditioned fear stress without elevation of glutamate,” Neuroscience Letters, vol. 379, no. 1, pp. 37–41, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. B. M. Spannuth, M. W. Hale, A. K. Evans, J. L. Lukkes, S. Campeau, and C. A. Lowry, “Investigation of a central nucleus of the amygdala/dorsal raphe nucleus serotonergic circuit implicated in fear-potentiated startle,” Neuroscience, vol. 179, pp. 104–119, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. K. J. Ressler and H. S. Mayberg, “Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic,” Nature Neuroscience, vol. 10, no. 9, pp. 1116–1124, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. J. R. Homberg, “The stress-coping (mis)match hypothesis for naturexnurture interactions,” Brain Research, vol. 1432, pp. 114–121, 2012. View at Publisher · View at Google Scholar
  7. J. E. LeDoux, “Molecular mechanisms of fear learning and memory,” Cell, vol. 147, no. 3, pp. 509–524, 2011. View at Publisher · View at Google Scholar
  8. M. E. Bouton, “Context, time, and memory retrieval in the interference paradigms of pavlovian learning,” Psychological Bulletin, vol. 114, no. 1, pp. 80–99, 1993. View at Google Scholar · View at Scopus
  9. M. Davis, W. A. Falls, S. Campeau, and M. Kim, “Fear-potentiated startle: a neural and pharmacological analysis,” Behavioural Brain Research, vol. 58, no. 1-2, pp. 175–198, 1993. View at Publisher · View at Google Scholar · View at Scopus
  10. C. Grillon, J. M. P. Baas, B. Cornwell, and L. Johnson, “Context conditioning and behavioral avoidance in a virtual reality environment: effect of predictability,” Biological Psychiatry, vol. 60, no. 7, pp. 752–759, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. D. Sierra-Mercado, N. Padilla-Coreano, and G. J. Quirk, “Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear,” Neuropsychopharmacology, vol. 36, no. 2, pp. 529–538, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. J. O'Keefe and D. H. Conway, “Hippocampal place units in the freely moving rat: why they fire where they fire,” Experimental Brain Research, vol. 31, no. 4, pp. 573–590, 1978. View at Google Scholar · View at Scopus
  13. K. A. Corcoran and S. Maren, “Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction,” Journal of Neuroscience, vol. 21, no. 5, pp. 1720–1726, 2001. View at Google Scholar · View at Scopus
  14. M. R. Milad, S. L. Rauch, R. K. Pitman, and G. J. Quirk, “Fear extinction in rats: implications for human brain imaging and anxiety disorders,” Biological Psychology, vol. 73, no. 1, pp. 61–71, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. K. M. Myers and M. Davis, “AX+, BX- discrimination learning in the fear-potentiated startle paradigm: possible relevance to inhibitory fear learning in extinction,” Learning and Memory, vol. 11, no. 4, pp. 464–475, 2004. View at Publisher · View at Google Scholar · View at Scopus
  16. J. M. Hitchcock and M. Davis, “Efferent pathway of the amygdala involved in conditioned fear as measured with the fear-potentiated startle paradigm,” Behavioral Neuroscience, vol. 105, no. 6, pp. 826–842, 1991. View at Publisher · View at Google Scholar · View at Scopus
  17. D. L. Walker, L. A. Miles, and M. Davis, “Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 33, no. 8, pp. 1291–1308, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. S. E. Hammack, K. J. Richey, L. R. Watkins, and S. F. Maier, “Chemical lesion of the bed nucleus of the stria terminalis blocks the behavioral consequences of uncontrollable stress,” Behavioral Neuroscience, vol. 118, no. 2, pp. 443–448, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. G. M. Sullivan, J. Apergis, D. E. A. Bush, L. R. Johnson, M. Hou, and J. E. Ledoux, “Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus,” Neuroscience, vol. 128, no. 1, pp. 7–14, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. J. Waddell, R. W. Morris, and M. E. Bouton, “Effects of bed nucleus of the stria terminalis lesions on conditioned anxiety: aversive conditioning with long-duration conditional stimuli and reinstatement of extinguished fear,” Behavioral Neuroscience, vol. 120, no. 2, pp. 324–336, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. R. P. Vertes, W. J. Fortin, and A. M. Crane, “Projections of the median raphe nucleus in the rat,” The Journal of Comparative Neurology, vol. 407, pp. 555–582, 1999. View at Publisher · View at Google Scholar
  22. R. Cools, A. C. Roberts, and T. W. Robbins, “Serotoninergic regulation of emotional and behavioural control processes,” Trends in Cognitive Sciences, vol. 12, no. 1, pp. 31–40, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. D. Natarajan, S. F. de Boer, and J. M. Koolhaas, “Lack of differential serotonin biosynthesis capacity in genetically selected low and high aggressive mice,” Physiology and Behavior, vol. 98, no. 4, pp. 411–415, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. P. Gaspar, O. Cases, and L. Maroteaux, “The developmental role of serotonin: news from mouse molecular genetics,” Nature Reviews Neuroscience, vol. 4, no. 12, pp. 1002–1012, 2003. View at Google Scholar · View at Scopus
  25. C. Kriegebaum, L. Gutknecht, A. Schmitt, K. P. Lesch, and A. Reif, “Serotonin now: part 1 neurobiology and developmental genetics,” Fortschritte der Neurologie Psychiatrie, vol. 78, no. 6, pp. 319–331, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. S. Tavoulari, L. R. Forrest, and G. Rudnick, “Fluoxetine (Prozac) binding to serotonin transporter is modulated by chloride and conformational changes,” Journal of Neuroscience, vol. 29, no. 30, pp. 9635–9643, 2009. View at Publisher · View at Google Scholar · View at Scopus
  27. J. F. Deakin, “Depression and 5HT,” International Clinical Psychopharmacology, vol. 6, supplement 3, pp. 23–28, 1991. View at Google Scholar
  28. E. W. Thornton and A. J. Goudie, “Evidence for the role of serotonin in the inihibition of specific motor responses,” Psychopharmacology, vol. 60, no. 1, pp. 73–79, 1978. View at Google Scholar · View at Scopus
  29. R. Cools, K. Nakamura, and N. D. Daw, “Serotonin and dopamine: unifying affective, activational, and decision functions,” Neuropsychopharmacology, vol. 36, no. 1, pp. 98–113, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. O. J. Robinson, C. Overstreet, P. S. Allen, D. S. Pine, and C. Grillon, “Acute tryptophan depletion increases translational indices of anxiety but not fear: serotonergic modulation of the bed nucleus of the stria terminalis?” Neuropsychopharmacology, vol. 37, pp. 1963–1971, 2012. View at Publisher · View at Google Scholar
  31. K. P. Lesch, D. Bengel, A. Heils et al., “Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region,” Science, vol. 274, no. 5292, pp. 1527–1531, 1996. View at Publisher · View at Google Scholar · View at Scopus
  32. B. T. Christian, A. S. Fox, J. A. Oler et al., “Serotonin transporter binding and genotype in the nonhuman primate brain using [C-11]DASB PET,” NeuroImage, vol. 47, no. 4, pp. 1230–1236, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. K. Shioe, T. Ichimiya, T. Suhara et al., “No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by pet,” Synapse, vol. 48, no. 4, pp. 184–188, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Willeit and N. Praschak-Rieder, “Imaging the effects of genetic polymorphisms on radioligand binding in the living human brain: a review on genetic neuroreceptor imaging of monoaminergic systems in psychiatry,” NeuroImage, vol. 53, no. 3, pp. 878–892, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. J. R. Homberg, D. Schubert, and P. Gaspar, “New perspectives on the neurodevelopmental effects of SSRIs,” Trends in Pharmacological Sciences, vol. 31, no. 2, pp. 60–65, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. A. R. Hariri, V. S. Mattay, A. Tessitore et al., “Serotonin transporter genetic variation and the response of the human amygdala,” Science, vol. 297, no. 5580, pp. 400–403, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. A. Heinz, D. F. Braus, M. N. Smolka et al., “Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter,” Nature Neuroscience, vol. 8, no. 1, pp. 20–21, 2005. View at Publisher · View at Google Scholar · View at Scopus
  38. L. Pezawas, A. Meyer-Lindenberg, E. M. Drabant et al., “5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression,” Nature Neuroscience, vol. 8, no. 6, pp. 828–834, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. M. D. Mochcovitch and A. E. Nardi, “Selective serotonin-reuptake inhibitors in the treatment of panic disorder: a systematic review of placebo-controlled studies,” Expert Review of Neurotherapeutics, vol. 10, no. 8, pp. 1285–1293, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. D. V. Sheehan and K. Kamijima, “An evidence-based review of the clinical use of sertraline in mood and anxiety disorders,” International Clinical Psychopharmacology, vol. 24, no. 2, pp. 43–60, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. B. Bandelow, D. J. Stein, O. T. Dolberg, H. F. Andersen, and D. S. Baldwin, “Improvement of quality of life in panic disorder with escitalopram, citalopram, or placebo,” Pharmacopsychiatry, vol. 40, no. 4, pp. 152–156, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. R. Invernizzi, M. Bramante, and R. Samanin, “Role of 5-HT1A receptors in the effects of acute and chronic fluoxetine on extracellular serotonin in the frontal cortex,” Pharmacology Biochemistry and Behavior, vol. 54, no. 1, pp. 143–147, 1996. View at Publisher · View at Google Scholar · View at Scopus
  43. V. Krishnan and E. J. Nestler, “The molecular neurobiology of depression,” Nature, vol. 455, no. 7215, pp. 894–902, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. N. S. Burghardt, G. M. Sullivan, B. S. McEwen, J. M. Gorman, and J. E. Ledoux, “The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine,” Biological Psychiatry, vol. 55, no. 12, pp. 1171–1178, 2004. View at Publisher · View at Google Scholar · View at Scopus
  45. L. P. Montezinho, S. Miller, N. Plath et al., “The effects of acute treatment with escitalopram on the different stages of contextual fear conditioning are reversed by atomoxetine,” Psychopharmacology, vol. 212, no. 2, pp. 131–143, 2010. View at Publisher · View at Google Scholar · View at Scopus
  46. C. Grillon, J. Levenson, and D. S. Pine, “A single dose of the selective serotonin reuptake inhibitor citalopram exacerbates anxiety in humans: a fear-potentiated startle study,” Neuropsychopharmacology, vol. 32, no. 1, pp. 225–231, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. C. Grillon, C. Chavis, M. F. Covington, and D. S. Pine, “Two-week treatment with the selective serotonin reuptake inhibitor citalopram reduces contextual anxiety but not cued fear in healthy volunteers: a fear-potentiated startle study,” Neuropsychopharmacology, vol. 34, no. 4, pp. 964–971, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. I. Muraki, T. Inoue, and T. Koyama, “Effect of co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 and selective 5-HT1B/1D receptor antagonist GR 127,935 on anxiolytic effect of citalopram in conditioned fear stress in the rat,” European Journal of Pharmacology, vol. 586, no. 1–3, pp. 171–178, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. N. S. Burghardt, D. E. A. Bush, B. S. McEwen, and J. E. LeDoux, “Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT2C receptor antagonist,” Biological Psychiatry, vol. 62, no. 10, pp. 1111–1118, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. C. M. Fattaccini, F. Bolanos-Jimenez, H. Gozlan, and M. Hamon, “Tianeptine stimulates uptake of 5-hydroxytryptamine in vivo in the rat brain,” Neuropharmacology, vol. 29, no. 1, pp. 1–8, 1990. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Hashimoto, T. Inoue, and T. Koyama, “Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats,” Psychopharmacology, vol. 123, no. 2, pp. 182–186, 1996. View at Publisher · View at Google Scholar · View at Scopus
  52. H. Nishikawa, T. Inoue, T. Izumi, and T. Koyama, “Synergistic effects of tandospirone and selective serotonin reuptake inhibitors on the contextual conditioned fear stress response in rats,” European Neuropsychopharmacology, vol. 17, no. 10, pp. 643–650, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. J. M. Santos, R. C. R. Martinez, and M. L. Brandão, “Effects of acute and subchronic treatments with fluoxetine and desipramine on the memory of fear in moderate and high-intensity contextual conditioning,” European Journal of Pharmacology, vol. 542, no. 1–3, pp. 121–128, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. S. Hashimoto, T. Inoue, I. Muraki, and T. Koyama, “Effects of acute citalopram on the expression of conditioned freezing in naive versus chronic citalopram-treated rats,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 33, no. 1, pp. 113–117, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. G. Spennato, C. Zerbib, C. Mondadori, and R. Garcia, “Fluoxetine protects hippocampal plasticity during conditioned fear stress and prevents fear learning potentiation,” Psychopharmacology, vol. 196, no. 4, pp. 583–589, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. R. C. B. Silva, A. C. Gárgaro, and M. L. Brandão, “Differential regulation of the expression of contextual freezing and fear-potentiated startle by 5-HT mechanisms of the median raphe nucleus,” Behavioural Brain Research, vol. 151, no. 1-2, pp. 93–101, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. Y. Ohmura, T. Izumi, T. Yamaguchi, I. Tsutsui-Kimura, T. Yoshida, and M. Yoshioka, “The serotonergic projection from the median raphe nucleus to the ventral hippocampus is involved in the retrieval of fear memory through the corticotropin-releasing factor type 2 receptor,” Neuropsychopharmacology, vol. 35, no. 6, pp. 1271–1278, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. R. Y. Wang and G. K. Aghajanian, “Antidromically identified serotonergic neurons in the rat midbrain raphe: evidence for collateral inhibition,” Brain Research, vol. 132, no. 1, pp. 186–193, 1977. View at Publisher · View at Google Scholar · View at Scopus
  59. S. H. Wang, L. de Oliveira Alvares, and K. Nader, “Cellular and systems mechanisms of memory strength as a constraint on auditory fear reconsolidation,” Nature Neuroscience, vol. 12, no. 7, pp. 905–912, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. O. Deschaux, H. Motanis, G. Spennato, J. L. Moreau, and R. Garcia, “Re-emergence of extinguished auditory-cued conditioned fear following a sub-conditioning procedure: effects of hippocampal and prefrontal tetanic stimulations,” Neurobiology of Learning and Memory, vol. 95, no. 4, pp. 510–518, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. N. N. Karpova, A. Pickenhagen, J. Lindholm et al., “Fear erasure in mice requires synergy between antidepressant drugs and extinction training,” Science, vol. 334, no. 6063, pp. 1731–1734, 2011. View at Publisher · View at Google Scholar
  62. M. C. Camp, K. P. Macpherson, L. Lederle et al., “Genetic strain differences in learned fear inhibition associated with variation in neuroendocrine, autonomic, and amygdala dendritic phenotypes,” Neuropsychopharmacology, vol. 37, pp. 1534–1547, 2012. View at Publisher · View at Google Scholar
  63. X. F. Huang, Y. Y. Tan, X. Huang, and Q. Wang, “Effect of chronic treatment with clozapine and haloperidol on 5-HT2A and 2C receptor mRNA expression in the rat brain,” Neuroscience Research, vol. 59, no. 3, pp. 314–321, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. C. Stein, H. Davidowa, and D. Albrecht, “5-HT(1A) receptor-mediated inhibition and 5-HT2 as well as 5-HT3 receptor-mediated excitation in different subdivisions of the rat amygdala,” Synapse, vol. 38, no. 3, pp. 328–337, 2000. View at Google Scholar · View at Scopus
  65. E. Lacivita, M. Leopoldo, F. Berardi, and R. Perrone, “5-HT1A receptor, an old target for new therapeutic agents,” Current Topics in Medicinal Chemistry, vol. 8, no. 12, pp. 1024–1034, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. O. Stiedl, I. Misane, J. Spiess, and S. O. Ogren, “Involvement of the 5-HT(1A) receptors in classical fear conditioning in C57BL/6J mice,” Journal of Neuroscience, vol. 20, no. 22, pp. 8515–8527, 2000. View at Google Scholar · View at Scopus
  67. H. Koseki, M. Matsumoto, H. Togashi, Y. Miura, K. Fukushima, and M. Yoshioka, “Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models,” Synapse, vol. 63, no. 9, pp. 805–813, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. S. E. Gartside, E. M. Clifford, P. J. Cowen, and T. Sharp, “Effects of (-)-tertatolol, (-)-penbutolol and (±)-pindolol in combination with paroxetine on presynaptic 5-HT function: an in vivo microdialysis and electrophysiological study,” British Journal of Pharmacology, vol. 127, no. 1, pp. 145–152, 1999. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Dong, C. de Montigny, and P. Blier, “Effect of acute and repeated versus sustained administration of the 5-HT(1A) receptor agonist ipsapirone: electrophysiological studies in the rat hippocampus and dorsal raphe,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 356, no. 3, pp. 303–311, 1997. View at Publisher · View at Google Scholar · View at Scopus
  70. H. Nishikawa, T. Inoue, T. Masui, T. Izumi, S. Nakagawa, and T. Koyama, “Pharmacokinetic interaction between tandospirone and fluvoxamine in the rat contextual conditioned fear stress model and its functional consequence: involvement of cytochrome P450 3A4,” Psychiatry and Clinical Neurosciences, vol. 62, no. 5, pp. 591–596, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. K. Nakamura and M. Kurasawa, “Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism,” European Journal of Pharmacology, vol. 420, no. 1, pp. 33–43, 2001. View at Publisher · View at Google Scholar · View at Scopus
  72. X. B. Li, T. Inoue, S. Hashimoto, and T. Koyama, “Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear,” European Journal of Pharmacology, vol. 425, no. 1, pp. 43–50, 2001. View at Publisher · View at Google Scholar · View at Scopus
  73. J. Youn, I. Misane, T. M. Eriksson et al., “Bidirectional modulation of classical fear conditioning in mice by 5-HT1A receptor ligands with contrasting intrinsic activities,” Neuropharmacology, vol. 57, no. 5-6, pp. 567–576, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. K. G. Borelli, C. Ferreira-Netto, and M. L. Brandão, “Distribution of Fos immunoreactivity in the rat brain after freezing or escape elicited by inhibition of glutamic acid decarboxylase or antagonism of GABA-A receptors in the inferior colliculus,” Behavioural Brain Research, vol. 170, no. 1, pp. 84–93, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. X. Li, T. Inoue, T. Abekawa et al., “5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala,” European Journal of Pharmacology, vol. 532, no. 1-2, pp. 74–80, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. L. Groenink, R. J. E. Joordens, T. H. Hijzen, A. Dirks, and B. Olivier, “Infusion of flesinoxan into the amygdala blocks the fear-potentiated startle,” NeuroReport, vol. 11, no. 10, pp. 2285–2288, 2000. View at Google Scholar · View at Scopus
  77. R. C. Almada, K. G. Borelli, L. Albrechet-Souza, and M. L. Brandão, “Serotonergic mechanisms of the median raphe nucleus-dorsal hippocampus in conditioned fear: output circuit involves the prefrontal cortex and amygdala,” Behavioural Brain Research, vol. 203, no. 2, pp. 279–287, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. K. Tada, K. Kasamo, T. Suzuki, Y. Matsuzaki, and T. Kojima, “Endogenous 5-HT inhibits firing activity of hippocampal CA1 pyramidal neurons during conditioned fear stress-induced freezing behavior through stimulating 5-HT1A receptors,” Hippocampus, vol. 14, no. 2, pp. 143–147, 2004. View at Publisher · View at Google Scholar · View at Scopus
  79. T. Sharp, L. Boothman, J. Raley, and P. Quérée, “Important messages in the “post”: recent discoveries in 5-HT neurone feedback control,” Trends in Pharmacological Sciences, vol. 28, no. 12, pp. 629–636, 2007. View at Publisher · View at Google Scholar · View at Scopus
  80. H. Hasuo, T. Matsuoka, and T. Akasu, “Activation of presynaptic 5-hydroxytryptamine 2A receptors facilitates excitatory synaptic transmission via protein kinase C in the dorsolateral septal nucleus,” Journal of Neuroscience, vol. 22, no. 17, pp. 7509–7517, 2002. View at Google Scholar · View at Scopus
  81. M. Wagner, A. Schuhmacher, S. Schwab, A. Zobel, and W. Maier, “The His452Tyr variant of the gene encoding the 5-HT2A receptor is specifically associated with consolidation of episodic memory in humans,” International Journal of Neuropsychopharmacology, vol. 11, no. 8, pp. 1163–1167, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. G. Zhang, H. N. Sgeirsdóttir, S. J. Cohen, A. H. Munchow, M. P. Barrera, and R. W. Stackman Jr., “Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice,” Neuropharmacology, vol. 64, pp. 403–413, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. N. V. Weisstaub, M. Zhou, A. Lira et al., “Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice,” Science, vol. 313, no. 5786, pp. 536–540, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. S. Liu, M. J. Bubar, M. F. Lanfranco, G. R. Hillman, and K. A. Cunningham, “Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: implications for understanding the neurobiology of addiction,” Neuroscience, vol. 146, no. 4, pp. 1677–1688, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. J. R. Martin, T. M. Ballard, and G. A. Higgins, “Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety,” Pharmacology Biochemistry and Behavior, vol. 71, no. 4, pp. 615–625, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. A. V. Metz, J. Chynoweth, and A. M. Allan, “Influence of genetic background on alcohol drinking and behavioral phenotypes of 5-HT3 receptor over-expressing mice,” Pharmacology Biochemistry and Behavior, vol. 84, no. 1, pp. 120–127, 2006. View at Publisher · View at Google Scholar · View at Scopus
  87. A. V. Harrell and A. M. Allan, “Improvements in hippocampal-dependent learning and decremental attention in 5-HT3 receptor overexpressing mice,” Learning and Memory, vol. 10, no. 5, pp. 410–419, 2003. View at Publisher · View at Google Scholar · View at Scopus
  88. S. Bhatnagar, N. Nowak, L. Babich, and L. Bok, “Deletion of the 5-HT3 receptor differentially affects behavior of males and females in the Porsolt forced swim and defensive withdrawal tests,” Behavioural Brain Research, vol. 153, no. 2, pp. 527–535, 2004. View at Publisher · View at Google Scholar · View at Scopus
  89. M. E. Nevins and E. W. Anthony, “Antagonists at the serotonin-3 receptor can reduce the fear-potentiated startle response in the rat: evidence for different types of anxiolytic activity?” Journal of Pharmacology and Experimental Therapeutics, vol. 268, no. 1, pp. 248–254, 1994. View at Google Scholar · View at Scopus
  90. M. Yoshioka, M. Matsumoto, H. Togashi, and H. Saito, “Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex,” Pharmacology Biochemistry and Behavior, vol. 51, no. 2-3, pp. 515–519, 1995. View at Publisher · View at Google Scholar · View at Scopus
  91. A. J. Roberts, T. Krucker, C. L. Levy, K. A. Slanina, J. G. Sutcliffe, and P. B. Hedlund, “Mice lacking 5-HT7 receptors show specific impairments in contextual learning,” European Journal of Neuroscience, vol. 19, no. 7, pp. 1913–1922, 2004. View at Publisher · View at Google Scholar · View at Scopus
  92. M. R. Munafò, T. G. Clark, K. H. Roberts, and E. C. Johnstone, “Neuroticism mediates the association of the serotonin transporter gene with lifetime major depression,” Neuropsychobiology, vol. 53, no. 1, pp. 1–8, 2006. View at Publisher · View at Google Scholar · View at Scopus
  93. M. C. Eker, O. Kitis, H. Okur et al., “Smaller hippocampus volume is associated with short variant of 5-HTTLPR polymorphism in medication-free major depressive disorder patients,” Neuropsychobiology, vol. 63, no. 1, pp. 22–28, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. T. Frodl, P. Zill, T. Baghai et al., “Reduced hippocampal volumes associated with the long variant of the tri- and diallelic serotonin transporter polymorphism in major depression,” American Journal of Medical Genetics B, vol. 147, no. 7, pp. 1003–1007, 2008. View at Publisher · View at Google Scholar · View at Scopus
  95. S. Gyawali, R. Subaran, M. M. Weissman et al., “Association of a polyadenylation polymorphism in the serotonin transporter and panic disorder,” Biological Psychiatry, vol. 67, no. 4, pp. 331–338, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. S. Battersby, A. D. Ogilvie, D. H. R. Blackwood et al., “Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3′ untranslated region of the human serotonin transporter gene,” Journal of Neurochemistry, vol. 72, no. 4, pp. 1384–1388, 1999. View at Publisher · View at Google Scholar · View at Scopus
  97. S. Z. Sabol, S. Hu, and D. Hamer, “A functional polymorphism in the monoamine oxidase A gene promoter,” Human Genetics, vol. 103, no. 3, pp. 273–279, 1998. View at Publisher · View at Google Scholar · View at Scopus
  98. A. Meyer-Lindenberg, J. W. Buckholtz, B. Kolachana et al., “Neural mechanisms of genetic risk for impulsivity and violence in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 16, pp. 6269–6274, 2006. View at Publisher · View at Google Scholar · View at Scopus
  99. N. Alia-Klein, R. Z. Goldstein, A. Kriplani et al., “Brain monoamine oxidase A activity predicts trait aggression,” Journal of Neuroscience, vol. 28, no. 19, pp. 5099–5104, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. H. Garpenstrand, P. Annas, J. Ekblom, L. Oreland, and M. Fredrikson, “Human fear conditioning is related to dopaminergic and serotonergic biological markers,” Behavioral Neuroscience, vol. 115, no. 2, pp. 358–364, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. F. Klumpers, D. Denys, J. L. Kenemans, C. Grillon, A. J. van der, and J. M. Baas, “Testing the effects of Delta9-THC and D-cycloserine on extinction of conditioned fear in humans,” Journal of Psychopharmacology, vol. 26, no. 4, pp. 471–478, 2012. View at Publisher · View at Google Scholar
  102. T. B. Lonsdorf, A. I. Weike, P. Nikamo, M. Schalling, A. O. Hamm, and A. Öhman, “Genetic gating of human fear learning and extinction: possible implications for gene-environment interaction in anxiety disorder,” Psychological Science, vol. 20, no. 2, pp. 198–206, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. B. Brocke, D. Armbruster, J. Müller et al., “Serotonin transporter gene variation impacts innate fear processing: acoustic startle response and emotional startle,” Molecular Psychiatry, vol. 11, no. 12, pp. 1106–1112, 2006. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Olsson and E. A. Phelps, “Social learning of fear,” Nature Neuroscience, vol. 10, no. 9, pp. 1095–1102, 2007. View at Publisher · View at Google Scholar · View at Scopus
  105. L. G. Crişan, S. Panǎ, R. Vulturar et al., “Genetic contributions of the serotonin transporter to social learning of fear and economic decision making,” Social Cognitive and Affective Neuroscience, vol. 4, no. 4, pp. 399–408, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. C. A. Hartley, M. C. McKenna, R. Salman et al., “Serotonin transporter polyadenylation polymorphism modulates the retention of fear extinction memory,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 14, pp. 5493–5498, 2012. View at Publisher · View at Google Scholar · View at Scopus
  107. T. Klucken, N. Alexander, J. Schweckendiek et al., “Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events,” Social Cognitive and Affective Neuroscience. In press. View at Publisher · View at Google Scholar
  108. I. Indovina, T. W. Robbins, A. O. Núñez-Elizalde, B. D. Dunn, and S. J. Bishop, “Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans,” Neuron, vol. 69, no. 3, pp. 563–571, 2011. View at Publisher · View at Google Scholar · View at Scopus
  109. C. Avshalom, A. R. Hariri, H. Andrew, R. Uher, and T. E. Moffitt, “Genetic sensitivity to the environment: The case of the serotonin transporter gene and its implications for studying complex diseases and traits,” American Journal of Psychiatry, vol. 167, no. 5, pp. 509–527, 2010. View at Publisher · View at Google Scholar · View at Scopus
  110. A. V. Kalueff, J. D. A. Olivier, L. J. P. Nonkes, and J. R. Homberg, “Conserved role for the serotonin transporter gene in rat and mouse neurobehavioral endophenotypes,” Neuroscience and Biobehavioral Reviews, vol. 34, no. 3, pp. 373–386, 2010. View at Publisher · View at Google Scholar · View at Scopus
  111. L. J. P. Nonkes, M. de Pooter, and J. R. Homberg, “Behavioural therapy based on distraction alleviates impaired fear extinction in male serotonin transporter knockout rats,” Journal of Psychiatry and Neuroscience, vol. 37, no. 4, pp. 224–230, 2012. View at Publisher · View at Google Scholar · View at Scopus
  112. P. Schipper, L. J. P. Nonkes, P. Karel, A. J. Kiliaan, and J. R. Homberg, “Serotonin transporter genotype x construction stress interaction in rats,” Behavioural Brain Research, vol. 223, no. 1, pp. 169–175, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. R. D. Pang, Z. Wang, L. P. Klosinski et al., “Mapping functional brain activation using [14C]-iodoantipyrine in male serotonin transporter knockout mice,” PLoS ONE, vol. 6, no. 8, Article ID Article numbere23869, 2011. View at Publisher · View at Google Scholar · View at Scopus
  114. C. L. Wellman, A. Izquierdo, J. E. Garrett et al., “Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice,” Journal of Neuroscience, vol. 27, no. 3, pp. 684–691, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. V. Narayanan, R. S. Heiming, F. Jansen et al., “Social defeat: Impact on fear extinction and Amygdala-prefrontal cortical theta synchrony in 5-HTT deficient mice,” PLoS ONE, vol. 6, no. 7, Article ID e22600, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. J. M. Muller, E. Morelli, M. Ansorge, and J. A. Gingrich, “Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks,” Genes, Brain and Behavior, vol. 10, no. 2, pp. 166–175, 2011. View at Publisher · View at Google Scholar · View at Scopus
  117. J. J. Kim, J. C. Shih, K. Chen et al., “Selective enhancement of emotional, but not motor, learning in monoamine oxidase A-deficient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 11, pp. 5929–5933, 1997. View at Publisher · View at Google Scholar · View at Scopus
  118. S. N. Young, S. E. Smith, R. O. Pihl, and F. R. Ervin, “Tryptophan depletion causes a rapid lowering of mood in normal males,” Psychopharmacology, vol. 87, no. 2, pp. 173–177, 1985. View at Google Scholar · View at Scopus
  119. E. Jéquier, W. Lovenberg, and A. Sjoerdsma, “Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine depletes rat brain serotonin,” Molecular Pharmacology, vol. 3, no. 3, pp. 274–278, 1967. View at Google Scholar · View at Scopus
  120. H. G. Baumgarten and A. Björklund, “Neurotoxic indoleamines and monoamine neurons,” Annual Review of Pharmacology and Toxicology, vol. 16, pp. 101–111, 1976. View at Google Scholar · View at Scopus
  121. Y. Q. Ding, U. Marklund, W. Yuan et al., “Lmx1b is essential for the development of serotonergic neurons,” Nature Neuroscience, vol. 6, no. 9, pp. 933–938, 2003. View at Publisher · View at Google Scholar · View at Scopus
  122. Z. Q. Zhao, S. Chiechio, Y. G. Sun et al., “Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs,” Journal of Neuroscience, vol. 27, no. 22, pp. 6045–6053, 2007. View at Publisher · View at Google Scholar · View at Scopus
  123. S. Uchida, Y. Kato, K. Hirano, Y. Kagawa, and S. Yamada, “Brain neurotransmitter receptor-binding characteristics in rats after oral administration of haloperidol, risperidone and olanzapine,” Life Sciences, vol. 80, no. 17, pp. 1635–1640, 2007. View at Publisher · View at Google Scholar · View at Scopus
  124. C. R. Hughes and N. B. Keele, “Phenytoin normalizes exaggerated fear behavior in p-chlorophenylalanine (PCPA)-treated rats,” Epilepsy and Behavior, vol. 9, no. 4, pp. 557–563, 2006. View at Publisher · View at Google Scholar · View at Scopus
  125. T. Archer, “Serotonin and fear retention in the rat,” Journal of Comparative and Physiological Psychology, vol. 96, no. 3, pp. 491–516, 1982. View at Publisher · View at Google Scholar · View at Scopus
  126. P. Rok-Bujko, P. Krzaścik, J. Szyndler, W. Kostowski, and R. Stefański, “The influence of neonatal serotonin depletion on emotional and exploratory behaviours in rats,” Behavioural Brain Research, vol. 226, no. 1, pp. 87–95, 2012. View at Publisher · View at Google Scholar · View at Scopus
  127. J. X. Dai, H. L. Han, M. Tian et al., “Enhanced contextual fear memory in central serotonin-deficient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, pp. 11981–11986, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. M. Yamauchi, T. Miyara, T. Matsushima, and T. Imanishi, “Desensitization of 5-HT2A receptor function by chronic administration of selective serotonin reuptake inhibitors,” Brain Research, vol. 1067, no. 1, pp. 164–169, 2006. View at Publisher · View at Google Scholar · View at Scopus
  129. S. F. Maier and L. R. Watkins, “Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor,” Neuroscience and Biobehavioral Reviews, vol. 29, no. 4-5, pp. 829–841, 2005. View at Publisher · View at Google Scholar · View at Scopus
  130. M. V. Baratta, T. R. Lucero, J. Amat, L. R. Watkins, and S. F. Maier, “Role of the ventral medial prefrontal cortex in mediating behavioral control-induced reduction of later conditioned fear,” Learning and Memory, vol. 15, no. 2, pp. 84–87, 2008. View at Publisher · View at Google Scholar · View at Scopus
  131. R. B. Mailman and V. Murthy, “Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?” Current Pharmaceutical Design, vol. 16, no. 5, pp. 488–501, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. G. K. Aghajanian and G. J. Marek, “Serotonin and hallucinogens,” Neuropsychopharmacology, vol. 21, no. 2, pp. 16S–23S, 1999. View at Publisher · View at Google Scholar · View at Scopus
  133. S. I. Reed, “First-episode psychosis: a literature review,” International Journal of Mental Health Nursing, vol. 17, no. 2, pp. 85–91, 2008. View at Publisher · View at Google Scholar · View at Scopus
  134. L. Günther, S. Liebscher, M. Jähkel, and J. Oehler, “Effects of chronic citalopram treatment on 5-HT1A and 5-HT2A receptors in group- and isolation-housed mice,” European Journal of Pharmacology, vol. 593, no. 1-3, pp. 49–61, 2008. View at Publisher · View at Google Scholar · View at Scopus
  135. A. Gobert and M. J. Millan, “Serotonin (5-HT)(2A) receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats,” Neuropharmacology, vol. 38, no. 2, pp. 315–317, 1999. View at Publisher · View at Google Scholar · View at Scopus
  136. V. Di Matteo, A. de Blasi, C. Di Giulio, and E. Esposito, “Role of 5-HT2C receptors in the control of central dopamine function,” Trends in Pharmacological Sciences, vol. 22, no. 5, pp. 229–232, 2001. View at Publisher · View at Google Scholar · View at Scopus
  137. P. de Deurwaerdère, S. Navailles, K. A. Berg, W. P. Clarke, and U. Spampinato, “Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens,” Journal of Neuroscience, vol. 24, no. 13, pp. 3235–3241, 2004. View at Publisher · View at Google Scholar · View at Scopus
  138. G. Porras, V. Di Matteo, C. Fracasso et al., “5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum,” Neuropsychopharmacology, vol. 26, no. 3, pp. 311–324, 2002. View at Publisher · View at Google Scholar · View at Scopus
  139. P. J. Fletcher, A. D. Lê, and G. A. Higgins, “Serotonin receptors as potential targets for modulation of nicotine use and dependence,” Progress in Brain Research, vol. 172, pp. 361–383, 2008. View at Publisher · View at Google Scholar · View at Scopus
  140. L. J. P. Nonkes, K. Tomson, A. Mærtin, J. Dederen, J. H. Roald Maes, and J. Homberg, “Orbitofrontal cortex and amygdalar over-activity is associated with an inability to use the value of expected outcomes to guide behaviour in serotonin transporter knockout rats,” Neurobiology of Learning and Memory, vol. 94, no. 1, pp. 65–72, 2010. View at Publisher · View at Google Scholar · View at Scopus
  141. L. J. P. Nonkes, J. H. R. Maes, and J. R. Homberg, “Improved cognitive flexibility in serotonin transporterknockout rats is unchanged following chronic cocaine self-administration,” Addiction Biology. In press. View at Publisher · View at Google Scholar · View at Scopus
  142. L. J. P. Nonkes, I. I. G. M. van de Vondervoort, M. J. C. de Leeuw, L. P. Wijlaars, J. H. R. Maes, and J. R. Homberg, “Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition,” Learning and Memory, vol. 19, no. 5, pp. 190–193, 2012. View at Publisher · View at Google Scholar · View at Scopus
  143. A. Lothe, C. Boni, N. Costes et al., “Association between triallelic polymorphism of the serotonin transporter and [18F]MPPF binding potential at 5-HT1A receptors in healthy subjects,” NeuroImage, vol. 47, no. 2, pp. 482–492, 2009. View at Publisher · View at Google Scholar · View at Scopus