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

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Artigas F (1995) Pindolol, 5-hydroxytryptamine, and antidepressant augmentation. Arch Gen Psychiatry 52:969–971

    PubMed  Article  CAS  Google 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 125:2664–2669

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  4. Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R (2009) Vulnerability genes or plasticity genes? Mol Psychiatry 14:746–754

    PubMed  Article  CAS  Google 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) 146:400–412

    Article  CAS  Google 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 9:20

    PubMed  Article  Google 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 66:631–642

    PubMed  Article  CAS  Google Scholar 

  8. Bylesjo EI, Boman K, Wetterberg L (1996) Obesity treated with phototherapy: four case studies. Int J Eat Disord 20:443–446

    PubMed  Article  CAS  Google Scholar 

  9. Carlsson A, Svennerholm L, Winblad B (1980) Seasonal and circadian monoamine variations in human brains examined post mortem. Acta Psychiatr Scand Suppl 280:75–85

    PubMed  CAS  Google 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 301:386–389

    PubMed  Article  CAS  Google 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 40:672–679

    PubMed  Article  Google Scholar 

  12. Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1252

    PubMed  Article  CAS  Google 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) 118:72–81

    Article  CAS  Google 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 107:17433–17438

    PubMed  Article  CAS  Google 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 10:855–862

    PubMed  Article  Google Scholar 

  16. Crockett MJ, Clark L, Tabibnia G, Lieberman MD, Robbins TW (2008) Serotonin modulates behavioral reactions to unfairness. Science 320:1739

    PubMed  Article  CAS  Google Scholar 

  17. Davis M, Strachan DI, Kass E (1980) Excitatory and inhibitory effects of serotonin on sensorimotor reactivity measured with acoustic startle. Science 209:521–523

    PubMed  Article  CAS  Google Scholar 

  18. de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475

    PubMed  Article  Google 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 115:755–760

    PubMed  Article  CAS  Google 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 24:370–378

    PubMed  Article  CAS  Google 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):285–294

    Google 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 23:285–294

    Article  CAS  Google Scholar 

  23. Goodman AH (2000) Why genes don't count (for racial differences in health). Am J Public Health 90:1699–1702

    PubMed  Article  CAS  Google Scholar 

  24. Hamilton M (2009) Population genetics, 1st edn. John Wiley & Sons, Chichester

  25. Harmer CJ, Bhagwagar Z, Shelley N, Cowen PJ (2003) Contrasting effects of citalopram and reboxetine on waking salivary cortisol. Psychopharmacology (Berl) 167:112–114

    CAS  Google 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).

  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 60:397–407

    PubMed  Article  CAS  Google 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 3:26

    PubMed  Article  Google 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 8:20–21

    PubMed  Article  CAS  Google 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 155:1023–1028

    PubMed  CAS  Google 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 35:127–134

    PubMed  Article  CAS  Google 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 47:643–649

    PubMed  Article  CAS  Google 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 12:400–413

    PubMed  Article  CAS  Google Scholar 

  34. Homberg JR, Lesch KP (2011) Looking on the bright side of serotonin transporter gene variation. Biol Psychiatry 69:513–519

    PubMed  Article  CAS  Google Scholar 

  35. Hood SD, Hince DA, Robinson H, Cirillo M, Christmas D, Kaye JM (2006) Serotonin regulation of the human stress response. Psychoneuroendocrinology 31:1087–1097

    PubMed  Article  CAS  Google Scholar 

  36. Hornung JP (2003) The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26:331–343

    PubMed  Article  CAS  Google Scholar 

  37. Jacobs BL, Azmitia EC (1992) Structure and function of the brain serotonin system. Physiol Rev 72:165–229

    PubMed  CAS  Google 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 461–469

  39. Jacobs BL, Fornal CA (1999) Activity of serotonergic neurons in behaving animals. Neuropsychopharmacology 21:9S–15S

    PubMed  CAS  Google 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 67:1033–1039

    PubMed  Article  CAS  Google 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 45:280–285

    PubMed  Article  Google 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 13:1021–1027

    PubMed  Article  CAS  Google 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 68:444–454

    PubMed  Article  Google 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 46:823–833

    PubMed  Article  CAS  Google 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 32:123–128

    PubMed  Article  CAS  Google 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 51:755–762

    Article  Google 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 360:1840–1842

    PubMed  Article  CAS  Google Scholar 

  48. Leprohon CE, Anderson GH (1982) Relationships among maternal diet, serotonin metabolism at weaning, and protein selection of progeny. J Nutr 112:29–38

    PubMed  CAS  Google 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 274:1527–1531

    PubMed  Article  CAS  Google 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 104:1259–1266

    PubMed  Article  CAS  Google Scholar 

  51. Levitan RD (2007) The chronobiology and neurobiology of winter seasonal affective disorder. Dialogues Clin Neurosci 9:315–324

    PubMed  Google 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:e36513

    PubMed  Article  CAS  Google 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 476:58–61

    PubMed  Article  CAS  Google Scholar 

  54. Livingstone FB (1971) Malaria and human polymorphisms. Annu Rev Genet 5:33–64

    Article  Google Scholar 

  55. Lucki I (1998) The spectrum of behaviors influenced by serotonin. Biol Psychiatry 44:151–162

    PubMed  Article  CAS  Google Scholar 

  56. Mann JJ (2003) Neurobiology of suicidal behaviour. Nat Rev Neurosci 4:819–828

    PubMed  Article  CAS  Google Scholar 

  57. Marks GA, Speciale SG, Cobbey K, Roffwarg HP (1987) Serotonergic inhibition of the dorsal lateral geniculate nucleus. Brain Res 418:76–84

    PubMed  Article  CAS  Google 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) 106:401–407

    Article  CAS  Google Scholar 

  59. Meyer-Lindenberg A, Weinberger DR (2006) Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7:818–827

    PubMed  Article  CAS  Google 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) 152:390–397

    Article  CAS  Google 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 11:76

    PubMed  Article  CAS  Google Scholar 

  62. Munafo MR, Brown SM, Hariri AR (2008) Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 63:852–857

    PubMed  Article  CAS  Google Scholar 

  63. Munafo MR, Durrant C, Lewis G, Flint J (2009) Gene X environment interactions at the serotonin transporter locus. Biol Psychiatry 65:211–219

    PubMed  Article  CAS  Google 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 52:50–54

    PubMed  Article  CAS  Google 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 5:32–38

    PubMed  Article  CAS  Google 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;69:520–525

    Google 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 7:395–399

    PubMed  Article  CAS  Google 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 62:327–331

    PubMed  Article  CAS  Google 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 149–167

    Google 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 65:1072–1078

    PubMed  Article  Google 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 58:825–830

    PubMed  Article  CAS  Google 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 43:339–347

    PubMed  Article  CAS  Google 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 66:1035–1039

    PubMed  Article  CAS  Google Scholar 

  74. Raleigh MJ, Brammer GL, McGuire MT, Yuwiler A (1985) Dominant social status facilitates the behavioral effects of serotonergic agonists. Brain Res 348:274–282

    PubMed  Article  CAS  Google 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 114:635–639

    PubMed  Article  CAS  Google 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):1163–1175

    PubMed  Article  Google 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 301:2462–2471

    PubMed  Article  CAS  Google Scholar 

  78. Robbins TW (2005) Chemistry of the mind: neurochemical modulation of prefrontal cortical function. J Comp Neurol 493:140–146

    PubMed  Article  CAS  Google 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 3:175–177

    PubMed  Article  CAS  Google 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 142:163–170

    PubMed  CAS  Google 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 26:695–706

    PubMed  Article  CAS  Google 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 67:323–330

    PubMed  Article  Google 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 28:4528–4532

    PubMed  Article  CAS  Google 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 48:184–188

    PubMed  Article  CAS  Google Scholar 

  85. Simansky KJ (1996) Serotonergic control of the organization of feeding and satiety. Behav Brain Res 73:37–42

    PubMed  Article  CAS  Google Scholar 

  86. Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:13–25

    PubMed  Article  CAS  Google 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 161:525–531

    PubMed  Article  Google 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 1071:184–202

    PubMed  Article  CAS  Google 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 56:101–112

    PubMed  Article  CAS  Google Scholar 

  90. Watson KK, Ghodasra JH, Platt ML (2009) Serotonin transporter genotype modulates social reward and punishment in rhesus macaques. PloS One 4:e4156

    PubMed  Article  Google Scholar 

  91. Way BM, Taylor SE (2010) The serotonin transporter promoter polymorphism is associated with cortisol response to psychosocial stress. Biol Psychiatry 67:487–492

    PubMed  Article  CAS  Google Scholar 

  92. Wehr TA, Rosenthal NE (1989) Seasonality and affective illness. Am J Psychiatry 146:829–839

    PubMed  CAS  Google 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 36:163–172

    PubMed  Article  Google 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 8:942–946

    PubMed  Article  CAS  Google 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 33:1503–1513

    PubMed  Article  CAS  Google 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 50:8–12

    PubMed  Article  CAS  Google Scholar 

  97. Winkler D, Pjrek E, Iwaki R, Kasper S (2006a) Treatment of seasonal affective disorder. Expert Rev Neurother 6:1039–1048

    PubMed  Article  CAS  Google 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 9:215–219

    PubMed  Article  Google 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) 111:239–243

    Article  CAS  Google 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 550–627

    Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jan Kalbitzer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kalbitzer, J., Kalbitzer, U., Knudsen, G.M. et al. 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. Psychopharmacology 230, 333–343 (2013). https://doi.org/10.1007/s00213-013-3308-1

Download citation

Keywords

  • Serotonin
  • 5-HTT
  • 5-HTTLPR
  • Behavior
  • Seasonality
  • Intermediate phenotypes