Advertisement

Psychopharmacology

, Volume 230, Issue 3, pp 333–343 | Cite as

How the cerebral serotonin homeostasis predicts environmental changes: a model to explain seasonal changes of brain 5-HTT as intermediate phenotype of the 5-HTTLPR

  • Jan KalbitzerEmail author
  • Urs Kalbitzer
  • Gitte Moos Knudsen
  • Paul Cumming
  • Andreas Heinz
Review

Abstract

Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment of the expected “safety” of the environment; this response is obtained in part through serotonergic modulation of the hypothalamic–pituitary–adrenal (HPA) axis. We posit that the intermediate phenotype of the s-allele may properly be understood as mediating a trade-off, wherein increased responsiveness of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes with pronounced seasonal climatic changes, while this hypothesis does not rule out that genetic drift plays an additional or even exclusive role. We argue that s-allele manifests as an intermediate phenotype in terms of an increased responsiveness of the 5-HTT expression to number of daylight hours, which may serve as a stable surrogate marker of other environmental factors, such as availability of food and safety of the environment in populations that live closer to the geographic poles.

Keywords

Serotonin 5-HTT 5-HTTLPR Behavior Seasonality Intermediate phenotypes 

Notes

Acknowledgments

This study was supported in part by DFG FOR 1617. JK is deeply thankful to CL Licht for the inspiring discussions and to F Bermpohl for the scientific and financial (through BMBF-01GWSO61) support. UK is supported by the Leibniz Graduate School “Foundations of Primate Behaviour”.

Conflict of interest

Jan Kalbitzer, Urs Kalbitzer, Gitte Moos Knudsen, Paul Cumming, and Andreas Heinz reported no biomedical financial interests or potential conflicts of interest.

References

  1. Artigas F (1995) Pindolol, 5-hydroxytryptamine, and antidepressant augmentation. Arch Gen Psychiatry 52:969–971PubMedCrossRefGoogle Scholar
  2. Bagdy G, Calogero AE, Murphy DL, Szemeredi K (1989) Serotonin agonists cause parallel activation of the sympathoadrenomedullary system and the hypothalamo-pituitary-adrenocortical axis in conscious rats. Endocrinology 125:2664–2669PubMedCrossRefGoogle Scholar
  3. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedCrossRefGoogle Scholar
  4. Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R (2009) Vulnerability genes or plasticity genes? Mol Psychiatry 14:746–754PubMedCrossRefGoogle Scholar
  5. Bizot J, Le Bihan C, Puech AJ, Hamon M, Thiebot M (1999) Serotonin and tolerance to delay of reward in rats. Psychopharmacology (Berl) 146:400–412CrossRefGoogle Scholar
  6. Bjorksten KS, Kripke DF, Bjerregaard P (2009) Accentuation of suicides but not homicides with rising latitudes of Greenland in the sunny months. BMC Psychiatry 9:20PubMedCrossRefGoogle Scholar
  7. Brodie BB, Shore PA (1957) A concept for a role of serotonin and norepinephrine as chemical mediators in the brain. Ann N Y Acad Sci 66:631–642PubMedCrossRefGoogle Scholar
  8. Bylesjo EI, Boman K, Wetterberg L (1996) Obesity treated with phototherapy: four case studies. Int J Eat Disord 20:443–446PubMedCrossRefGoogle Scholar
  9. Carlsson A, Svennerholm L, Winblad B (1980) Seasonal and circadian monoamine variations in human brains examined post mortem. Acta Psychiatr Scand Suppl 280:75–85PubMedGoogle Scholar
  10. Caspi A, Sugden K, Moffitt T, Taylor A, Craig I, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389PubMedCrossRefGoogle Scholar
  11. Chakraborty S, Chakraborty D, Mukherjee O, Jain S, Ramakrishnan U, Sinha A (2010) Genetic polymorphism in the serotonin transporter promoter region and ecological success in macaques. Behav Genet 40:672–679PubMedCrossRefGoogle Scholar
  12. Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1252PubMedCrossRefGoogle Scholar
  13. Cleare AJ, Bond AJ (1995) The effect of tryptophan depletion and enhancement on subjective and behavioural aggression in normal male subjects. Psychopharmacology (Berl) 118:72–81CrossRefGoogle Scholar
  14. Crockett MJ, Clark L, Hauser MD, Robbins TW (2010a) Serotonin selectively influences moral judgment and behavior through effects on harm aversion. Proc Natl Acad Sci U S A 107:17433–17438PubMedCrossRefGoogle Scholar
  15. Crockett MJ, Clark L, Lieberman MD, Tabibnia G, Robbins TW (2010b) Impulsive choice and altruistic punishment are correlated and increase in tandem with serotonin depletion. Emotion 10:855–862PubMedCrossRefGoogle Scholar
  16. Crockett MJ, Clark L, Tabibnia G, Lieberman MD, Robbins TW (2008) Serotonin modulates behavioral reactions to unfairness. Science 320:1739PubMedCrossRefGoogle Scholar
  17. Davis M, Strachan DI, Kass E (1980) Excitatory and inhibitory effects of serotonin on sensorimotor reactivity measured with acoustic startle. Science 209:521–523PubMedCrossRefGoogle Scholar
  18. de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475PubMedCrossRefGoogle Scholar
  19. Esau L, Kaur M, Adonis L, Arieff Z (2008) The 5-HTTLPR polymorphism in South African healthy populations: a global comparison. J Neural Transm 115:755–760PubMedCrossRefGoogle Scholar
  20. Fairbanks LA, Melega WP, Jorgensen MJ, Kaplan JR, McGuire MT (2001) Social impulsivity inversely associated with CSF 5-HIAA and fluoxetine exposure in vervet monkeys. Neuropsychopharmacology 24:370–378PubMedCrossRefGoogle Scholar
  21. Frokjaer VG, Erritzoe D, Holst KK, Jensen PS, Rasmussen PM, Fisher PM, Baaré W, Madsen KS, Madsen J, Svarer C, Knudsen GM (2013) Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response. Eur Neuropsychopharmacology 23(4):285–294Google Scholar
  22. Frokjaer VG, Erritzoe D, Holst KK, Jensen PS, Rasmussen PM, Fisher PM, Baare W, Madsen KS, Madsen J, Svarer C, Knudsen GM (2013) Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response. Eur Neuropsychopharmacol: J Eur Coll Neuropsychopharmacol 23:285–294CrossRefGoogle Scholar
  23. Goodman AH (2000) Why genes don't count (for racial differences in health). Am J Public Health 90:1699–1702PubMedCrossRefGoogle Scholar
  24. Hamilton M (2009) Population genetics, 1st edn. John Wiley & Sons, ChichesterGoogle Scholar
  25. Harmer CJ, Bhagwagar Z, Shelley N, Cowen PJ (2003) Contrasting effects of citalopram and reboxetine on waking salivary cortisol. Psychopharmacology (Berl) 167:112–114Google Scholar
  26. Harris J, Chan S (2010) Moral behavior is not what it seems. Proceedings of the National Academy of Sciences of the United States of America 107: E183 (author reply E184).Google Scholar
  27. Heiming RS, Bodden C, Jansen F, Lewejohann L, Kaiser S, Lesch KP, Palme R, Sachser N (2011) Living in a dangerous world decreases maternal care: a study in serotonin transporter knockout mice. Horm Behav 60:397–407PubMedCrossRefGoogle Scholar
  28. Heiming RS, Jansen F, Lewejohann L, Kaiser S, Schmitt A, Lesch KP, Sachser N (2009) Living in a dangerous world: the shaping of behavioral profile by early environment and 5-HTT genotype. Front Behav Neurosci 3:26PubMedCrossRefGoogle Scholar
  29. Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grusser SM, Flor H, Schumann G, Mann K, Buchel C (2005) Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 8:20–21PubMedCrossRefGoogle Scholar
  30. Heinz A, Higley JD, Gorey JG, Saunders RC, Jones DW, Hommer D, Zajicek K, Suomi SJ, Lesch KP, Weinberger DR, Linnoila M (1998) In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates. Am J Psychiatry 155:1023–1028PubMedGoogle Scholar
  31. Heinz A, Jones DW, Bissette G, Hommer D, Ragan P, Knable M, Wellek S, Linnoila M, Weinberger DR (2002) Relationship between cortisol and serotonin metabolites and transporters in alcoholism [correction of alcolholism]. Pharmacopsychiatry 35:127–134PubMedCrossRefGoogle Scholar
  32. Heinz A, Jones DW, Mazzanti C, Goldman D, Ragan P, Hommer D, Linnoila M, Weinberger DR (2000) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 47:643–649PubMedCrossRefGoogle Scholar
  33. Heinz AJ, Beck A, Meyer-Lindenberg A, Sterzer P, Heinz A (2011) Cognitive and neurobiological mechanisms of alcohol-related aggression. Nat Rev Neurosci 12:400–413PubMedCrossRefGoogle Scholar
  34. Homberg JR, Lesch KP (2011) Looking on the bright side of serotonin transporter gene variation. Biol Psychiatry 69:513–519PubMedCrossRefGoogle Scholar
  35. Hood SD, Hince DA, Robinson H, Cirillo M, Christmas D, Kaye JM (2006) Serotonin regulation of the human stress response. Psychoneuroendocrinology 31:1087–1097PubMedCrossRefGoogle Scholar
  36. Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343PubMedCrossRefGoogle Scholar
  37. Jacobs BL, Azmitia EC (1992) Structure and function of the brain serotonin system. Physiol Rev 72:165–229PubMedGoogle Scholar
  38. Jacobs BL, Fornal CA (1995) Serotonin and behavior: a general hypothesis. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology the fourth generation of progress (associate editors, Benjamin S Bunney et al. in association with the American College of Neuropsychopharmacology). Raven Press, New York, pp 461–469Google Scholar
  39. Jacobs BL, Fornal CA (1999) Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology 21:9S–15SPubMedGoogle Scholar
  40. Kalbitzer J, Erritzoe D, Holst KK, Nielsen FA, Marner L, Lehel S, Arentzen T, Jernigan TL, Knudsen GM (2010) Seasonal changes in brain serotonin transporter binding in short serotonin transporter linked polymorphic region-allele carriers but not in long-allele homozygotes. Biol Psychiatry 67:1033–1039PubMedCrossRefGoogle Scholar
  41. Kalbitzer J, Frokjaer VG, Erritzoe D, Svarer C, Cumming P, Nielsen FA, Hashemi SH, Baare WF, Madsen J, Hasselbalch SG, Kringelbach ML, Mortensen EL, Knudsen GM (2009) The personality trait openness is related to cerebral 5-HTT levels. NeuroImage 45:280–285PubMedCrossRefGoogle Scholar
  42. Kalin NH, Shelton SE, Fox AS, Rogers J, Oakes TR, Davidson RJ (2008) The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. Mol Psychiatry 13:1021–1027PubMedCrossRefGoogle Scholar
  43. Karg K, Burmeister M, Shedden K, Sen S (2011) The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry 68:444–454PubMedCrossRefGoogle Scholar
  44. Kasper S, Wehr TA, Bartko JJ, Gaist PA, Rosenthal NE (1989) Epidemiological findings of seasonal changes in mood and behavior: a telephone survey of Montgomery County, Maryland. Arch Gen Psychiatry 46:823–833PubMedCrossRefGoogle Scholar
  45. Kish SJ, Furukawa Y, Chang LJ, Tong J, Ginovart N, Wilson A, Houle S, Meyer JH (2005) Regional distribution of serotonin transporter protein in postmortem human brain: is the cerebellum a SERT-free brain region? Nucl Med Biol 32:123–128PubMedCrossRefGoogle Scholar
  46. Kumsta R, Stevens S, Brookes K, Schlotz W, Castle J, Beckett C, Kreppner J, Rutter M, Sonuga-Barke E (2010) 5HTT genotype moderates the influence of early institutional deprivation on emotional problems in adolescence: evidence from the English and Romanian Adoptee (ERA) study. J Child Psychol Psychiatr Allied Discip 51:755–762CrossRefGoogle Scholar
  47. Lambert G, Reid C, Kaye D, Jennings G, Esler M (2002) Effect of sunlight and season on serotonin turnover in the brain. Lancet 360:1840–1842PubMedCrossRefGoogle Scholar
  48. Leprohon CE, Anderson GH (1982) Relationships among maternal diet, serotonin metabolism at weaning, and protein selection of progeny. J Nutr 112:29–38PubMedGoogle Scholar
  49. Lesch K, Bengel D, Heils A, Sabol S, Greenberg B, Petri S, Benjamin J, Müller C, Hamer D, Murphy D (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedCrossRefGoogle Scholar
  50. Lesch KP, Meyer J, Glatz K, Flugge G, Hinney A, Hebebrand J, Klauck SM, Poustka A, Poustka F, Bengel D, Mossner R, Riederer P, Heils A (1997) The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication. J Neural Transm 104:1259–1266PubMedCrossRefGoogle Scholar
  51. Levitan RD (2007) The chronobiology and neurobiology of winter seasonal affective disorder. Dialogues Clin Neurosci 9:315–324PubMedGoogle Scholar
  52. Li S, Zou Q, Li J, Li J, Wang D, Yan C, Dong Q, Zang YF (2012) 5-HTTLPR polymorphism impacts task-evoked and resting-state activities of the amygdala in Han Chinese. PloS One 7:e36513PubMedCrossRefGoogle Scholar
  53. Licht CL, Knudsen GM, Sharp T (2010) Effects of the 5-HT(4) receptor agonist RS67333 and paroxetine on hippocampal extracellular 5-HT levels. Neurosci Lett 476:58–61PubMedCrossRefGoogle Scholar
  54. Livingstone FB (1971) Malaria and human polymorphisms. Annu Rev Genet 5:33–64CrossRefGoogle Scholar
  55. Lucki I (1998) The spectrum of behaviors influenced by serotonin. Biol Psychiatry 44:151–162PubMedCrossRefGoogle Scholar
  56. Mann JJ (2003) Neurobiology of suicidal behaviour. Nat Rev Neurosci 4:819–828PubMedCrossRefGoogle Scholar
  57. Marks GA, Speciale SG, Cobbey K, Roffwarg HP (1987) Serotonergic inhibition of the dorsal lateral geniculate nucleus. Brain Res 418:76–84PubMedCrossRefGoogle Scholar
  58. McGuirk J, Muscat R, Willner P (1992) Effects of chronically administered fluoxetine and fenfluramine on food intake, body weight and the behavioural satiety sequence. Psychopharmacology (Berl) 106:401–407CrossRefGoogle Scholar
  59. Meyer-Lindenberg A, Weinberger DR (2006) Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7:818–827PubMedCrossRefGoogle Scholar
  60. Mobini S, Chiang TJ, Ho MY, Bradshaw CM, Szabadi E (2000) Effects of central 5-hydroxytryptamine depletion on sensitivity to delayed and probabilistic reinforcement. Psychopharmacology (Berl) 152:390–397CrossRefGoogle Scholar
  61. Morey RA, Hariri AR, Gold AL, Hauser MA, Munger HJ, Dolcos F, McCarthy G (2011) Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder. BMC Psychiatry 11:76PubMedCrossRefGoogle Scholar
  62. Munafo MR, Brown SM, Hariri AR (2008) Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 63:852–857PubMedCrossRefGoogle Scholar
  63. Munafo MR, Durrant C, Lewis G, Flint J (2009) Gene X environment interactions at the serotonin transporter locus. Biol Psychiatry 65:211–219PubMedCrossRefGoogle Scholar
  64. Murthy NV, Selvaraj S, Cowen PJ, Bhagwagar Z, Riedel WJ, Peers P, Kennedy JL, Sahakian BJ, Laruelle MA, Rabiner EA, Grasby PM (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain. NeuroImage 52:50–54PubMedCrossRefGoogle Scholar
  65. Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5:32–38PubMedCrossRefGoogle Scholar
  66. Pluess M, Velders FP, Belsky J, van Ijzendoorn MH, Bakermans-Kranenburg MJ, Jaddoe VW, Hofman A, Arp PP, Verhulst FC, Tiemeier H (2011) Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality. Biol Psychiatry 15;69:520–525Google Scholar
  67. Poulos CX, Parker JL, Le AD (1996) Dexfenfluramine and 8-OH-DPAT modulate impulsivity in a delay-of-reward paradigm: implications for a correspondence with alcohol consumption. Behav Pharmacol 7:395–399PubMedCrossRefGoogle Scholar
  68. Praschak-Rieder N, Kennedy J, Wilson AA, Hussey D, Boovariwala A, Willeit M, Ginovart N, Tharmalingam S, Masellis M, Houle S, Meyer JH (2007) Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study. Biol Psychiatry 62:327–331PubMedCrossRefGoogle Scholar
  69. Praschak-Rieder N, Willeit M (2012) Imaging of seasonal affective disorder and seasonality effects on serotonin and dopamine function in the human brain. In: Carter CS, Dalley JW (eds) Current topics in behavioral neurosciences, vol 11. Springer, Heidelberg, pp 149–167Google Scholar
  70. Praschak-Rieder N, Willeit M, Wilson A, Houle S, Meyer J (2008) Seasonal variation in human brain serotonin transporter binding. Arch Gen Psychiatry 65:1072–1078PubMedCrossRefGoogle Scholar
  71. Praschak-Rieder N, Wilson AA, Hussey D, Carella A, Wei C, Ginovart N, Schwarz MJ, Zach J, Houle S, Meyer JH (2005) Effects of tryptophan depletion on the serotonin transporter in healthy humans. Biol Psychiatry 58:825–830PubMedCrossRefGoogle Scholar
  72. Price LH, Malison RT, McDougle CJ, Pelton GH, Heninger GR (1998) The neurobiology of tryptophan depletion in depression: effects of intravenous tryptophan infusion. Biol Psychiatry 43:339–347PubMedCrossRefGoogle Scholar
  73. Quelch DR, Parker CA, Nutt DJ, Tyacke RJ, Erritzoe D (2012) Influence of different cellular environments on [(3)H]DASB radioligand binding. Synapse 66:1035–1039PubMedCrossRefGoogle Scholar
  74. Raleigh MJ, Brammer GL, McGuire MT, Yuwiler A (1985) Dominant social status facilitates the behavioral effects of serotonergic agonists. Brain Res 348:274–282PubMedCrossRefGoogle Scholar
  75. Reimold M, Smolka MN, Schumann G, Zimmer A, Wrase J, Mann K, Hu XZ, Goldman D, Reischl G, Solbach C, Machulla HJ, Bares R, Heinz A (2007) Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype. J Neural Transm 114:635–639PubMedCrossRefGoogle Scholar
  76. Ren C, Luan L, Wui-Man Lau B, Huang X, Yang J, Zhou Y, Wu X, Gao J, Pickard GE, So KF, Pu M (2013) Direct retino-raphe projection alters serotonergic tone and affective behavior. Neuropsychopharmacology 38(7):1163–1175PubMedCrossRefGoogle Scholar
  77. Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR (2009) Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301:2462–2471PubMedCrossRefGoogle Scholar
  78. Robbins TW (2005) Chemistry of the mind: neurochemical modulation of prefrontal cortical function. J Comp Neurol 493:140–146PubMedCrossRefGoogle Scholar
  79. Rosenthal NE, Mazzanti CM, Barnett RL, Hardin TA, Turner EH, Lam GK, Ozaki N, Goldman D (1998) Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder. Mol Psychiatry 3:175–177PubMedCrossRefGoogle Scholar
  80. Rosenthal NE, Sack DA, Carpenter CJ, Parry BL, Mendelson WB, Wehr TA (1985) Antidepressant effects of light in seasonal affective disorder. Am J Psychiatry 142:163–170PubMedGoogle Scholar
  81. Sarrias MJ, Artigas F, Martinez E, Gelpi E (1989) Seasonal changes of plasma serotonin and related parameters: correlation with environmental measures. Biol Psychiatry 26:695–706PubMedCrossRefGoogle Scholar
  82. Schwandt ML, Lindell SG, Sjoberg RL, Chisholm KL, Higley JD, Suomi SJ, Heilig M, Barr CS (2010) Gene-environment interactions and response to social intrusion in male and female rhesus macaques. Biol Psychiatry 67:323–330PubMedCrossRefGoogle Scholar
  83. Schweighofer N, Bertin M, Shishida K, Okamoto Y, Tanaka SC, Yamawaki S, Doya K (2008) Low-serotonin levels increase delayed reward discounting in humans. J Neurosci 28:4528–4532PubMedCrossRefGoogle Scholar
  84. Shioe K, Ichimiya T, Suhara T, Takano A, Sudo Y, Yasuno F, Hirano M, Shinohara M, Kagami M, Okubo Y, Nankai M, Kanba S (2003) No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse 48:184–188PubMedCrossRefGoogle Scholar
  85. Simansky KJ (1996) Serotonergic control of the organization of feeding and satiety. Behav Brain Res 73:37–42PubMedCrossRefGoogle Scholar
  86. Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:13–25PubMedCrossRefGoogle Scholar
  87. van Dyck CH, Malison RT, Staley JK, Jacobsen LK, Seibyl JP, Laruelle M, Baldwin RM, Innis RB, Gelernter J (2004) Central serotonin transporter availability measured with [123I]beta-CIT SPECT in relation to serotonin transporter genotype. Am J Psychiatry 161:525–531PubMedCrossRefGoogle Scholar
  88. Vermetten E, Vythilingam M, Schmahl C, DEK C, Southwick SM, Charney DS, Bremner JD (2006) Alterations in stress reactivity after long-term treatment with paroxetine in women with posttraumatic stress disorder. Ann N Y Acad Sci 1071:184–202PubMedCrossRefGoogle Scholar
  89. Vythilingam M, Vermetten E, Anderson GM, Luckenbaugh D, Anderson ER, Snow J, Staib LH, Charney DS, Bremner JD (2004) Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment. Biol Psychiatry 56:101–112PubMedCrossRefGoogle Scholar
  90. Watson KK, Ghodasra JH, Platt ML (2009) Serotonin transporter genotype modulates social reward and punishment in rhesus macaques. PloS One 4:e4156PubMedCrossRefGoogle Scholar
  91. Way BM, Taylor SE (2010) The serotonin transporter promoter polymorphism is associated with cortisol response to psychosocial stress. Biol Psychiatry 67:487–492PubMedCrossRefGoogle Scholar
  92. Wehr TA, Rosenthal NE (1989) Seasonality and affective illness. Am J Psychiatry 146:829–839PubMedGoogle Scholar
  93. Wendland JR, Lesch KP, Newman TK, Timme A, Gachot-Neveu H, Thierry B, Suomi SJ (2006) Differential functional variability of serotonin transporter and monoamine oxidase a genes in macaque species displaying contrasting levels of aggression-related behavior. Behav Genet 36:163–172PubMedCrossRefGoogle Scholar
  94. Willeit M, Praschak-Rieder N, Neumeister A, Zill P, Leisch F, Stastny J, Hilger E, Thierry N, Konstantinidis A, Winkler D, Fuchs K, Sieghart W, Aschauer H, Ackenheil M, Bondy B, Kasper S (2003) A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder. Mol Psychiatry 8:942–946PubMedCrossRefGoogle Scholar
  95. Willeit M, Sitte HH, Thierry N, Michalek K, Praschak-Rieder N, Zill P, Winkler D, Brannath W, Fischer MB, Bondy B, Kasper S, Singer EA (2008) Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology 33:1503–1513PubMedCrossRefGoogle Scholar
  96. Willeit M, Stastny J, Pirker W, Praschak-Rieder N, Neumeister A, Asenbaum S, Tauscher J, Fuchs K, Sieghart W, Hornik K, Aschauer H, Brücke T, Kasper S (2001) No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry 50:8–12PubMedCrossRefGoogle Scholar
  97. Winkler D, Pjrek E, Iwaki R, Kasper S (2006a) Treatment of seasonal affective disorder. Expert Rev Neurother 6:1039–1048PubMedCrossRefGoogle Scholar
  98. Winkler D, Pjrek E, Konstantinidis A, Praschak-Rieder N, Willeit M, Stastny J, Kasper S (2006b) Anger attacks in seasonal affective disorder. Int J Neuropsychopharmacol 9:215–219PubMedCrossRefGoogle Scholar
  99. Wogar MA, Bradshaw CM, Szabadi E (1993) Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on choice between delayed reinforcers. Psychopharmacology (Berl) 111:239–243CrossRefGoogle Scholar
  100. Zinner D, Fickenscher GH, Roos C (2013) Family Cercopithecidae (Old World Monkeys). In: Mittermeier RA, Rylands AB, Wilson EW (eds) Handbook of the mammals of the world, vol 3, Primates. Lynx Edicions, Barcelona, pp 550–627Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jan Kalbitzer
    • 1
    • 2
    Email author
  • Urs Kalbitzer
    • 3
  • Gitte Moos Knudsen
    • 4
  • Paul Cumming
    • 5
  • Andreas Heinz
    • 1
  1. 1.Department of Psychiatry and PsychotherapyCharité - Universitätsmedizin Berlin (Campus Mitte)BerlinGermany
  2. 2.Psychiatrische Universitätsklinik der CharitéIm St. Hedwig KrankenhausBerlinGermany
  3. 3.Cognitive Ethology Laboratory, German Primate CenterUniversity of GöttingenGöttingenGermany
  4. 4.Neurobiology Research Unit and Cimbi, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
  5. 5.Department of Nuclear MedicineFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany

Personalised recommendations