Abstract
Serotonin systems appear to play a key role in the pathophysiology of major depressive disorder. Consequently, ongoing research determines whether serotonin related genes account for the very robust differential behavioral and neural mechanisms that discriminate patients with depression from healthy controls. Serotonin type 1A receptors and the serotonin transporters are reduced in depression, and recent genetic research in animals and humans has implicated both in depression. Preclinical studies have utilized a variety of animal models that have been used to explain pathophysiological mechanisms in humans, although it is not clear at all whether these models constitute relevant models for depression in humans. However, data from preclinical studies can generate hypotheses that are tested in humans by combining genetic data with behavioral and physiological challenge paradigms and neuroimaging. These studies will enhance our understanding about combined influences from multiple interacting genes, as well as from environmental factors on brain circuits and their function, and about how these mechanisms may contribute to the pathophysiology of neuropsychiatric disorders.
Similar content being viewed by others
References
Abbott FV, Etienne P, Franklin KB, Morgan MJ, Sewitch MJ, Young SN (1992) Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans. Psychopharmacology 108:60–66
Arias B, Arranz MJ, Gasto C et al. (2002) Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT(1A) receptor gene as putative risk factors in major depression. Mol Psychiatry 7:930–932; Erratum in: Mol Psychiatry 8:246
Asberg M, Thoren P, Traskman L, Bertilsson L, Ringberger V (1976) “Serotonin depression”—a biochemical subgroup within the affective disorders? Science 191:478–480
Azmitia EC (1999) Serotonin neurons, neuroplasticity, and homeostasis of neural tissue. Neuropsychopharmacology 21:33S–45S
Azmitia EC, Whitaker-Azmitia PM (1991) Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system. J Clin Psychiatry 52 Suppl:4–16
Azmitia EC, Gannon PJ, Kheck NM, Whitaker-Azmitia PM (1996) Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology 14:35–46
Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152
Bellivier F, Laplanche JL, Leboyer M et al. (1997) Serotonin transporter gene and manic depressive illness: an association study. Biol Psychiatry 41:750–752
Bellivier F, Szoke A, Henry C et al. (2000) Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders. Biol Psychiatry 48:319–322
Benkelfat C, Ellenbogen MA, Dean P, Palmour RM, Young SN (1994) Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry 51:687–697
Bhagwagar Z, Montgomery AJ, Grasby PM, Cowen PJ (2003) Lack of effect of a single dose of hydrocortisone on serotonin(1A) receptors in recovered depressed patients measured by positron emission tomography with [11C]WAY-100635. Biol Psychiatry 54:890–895
Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 9:386–392
Bondy B, Erfurth A, de Jonge S, Kruger M, Meyer H (2000) Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide. Mol Psychiatry 5:193–195
Bortolozzi A, Amargos-Bosch M, Toth M, Artigas F, Adell A (2004) In vivo efflux of serotonin in the dorsal raphe nucleus of 5-HT1A receptor knockout mice. J Neurochem 88:1373–1379
Carli M, Afkhami-Dastjerdian S, Reader TA (1996) [3H]8-OH-DPAT binding and serotonin content in rat cerebral cortex after acute fluoxetine, desipramine, or pargyline. J Psychiatr Neurosci 21:114–122
Carpenter LL, Anderson GM, Pelton GH et al. (1998) Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 19:26–35
Carpenter LL, Tyrka AR, McDougle CJ et al. (2004) Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects. Neuropsychopharmacology 29:777–784
Caspi A, Sugden K, Moffitt TE et al. (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389
Cloninger CR, Przybeck TR, Svrakic DM (1991) The tridimensional personality questionnaire: U.S. normative data. Psychol Rep 69:1047–1057
Collier DA, Stober G, Li T et al. (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460
Cook EH Jr, Courchesne R, Lord C et al. (1997) Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 2:247–250
Coppen A, Eccleston EG, Peet M (1973) Total and free tryptophan concentration in the plasma of depressive patients. Lancet 2:60–63
Courtet P, Buresi C, Abbar M et al. (2003) No association between non-violent suicidal behavior and the serotonin transporter promotor polymorphism. Am J Med Genet 1:72–76
Courtet P, Picot MC, Bellivier F et al. (2004) Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts. Biol Psychiatry 55:46–51
Cowen PJ, Charig EM (1987) Neuroendocrine responses to intravenous tryptophan in major depression. Arch Gen Psychiatry 44:958–966
Cowen PJ, Parry-Billings M, Newsholme EA (1989) Decreased plasma tryptophan levels in major depression. J Affect Disord 16:27–31
Czyrak A, Czepiel K, Mackowiak M, Chocyk A, Wedzony K (2003) Serotonin 5-HT1A receptors might control the output of cortical glutamatergic neurons in rat cingulate cortex. Brain Res 989:42–51
Drevets WC, Frank E, Price JC et al. (1999) PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46:1375–1387
Ebstein RP, Gritsenko I, Nemanov L, Frisch A, Osher Y, Belmaker RH (1997) No association between the serotonin transporter gene regulatory region polymorphism and the Tridimensional Personality Questionnaire (TPQ) temperament of harm avoidance. Mol Psychiatry 2:224–226
Egede LE (2004) Diabetes, major depression, and functional disability among U.S. adults. Diabetes Care 27:421–428
Erdmann J, Shimron-Abarbanell D, Cichon S et al. (1995) Systematic screening for mutations in the promoter and the coding region of the 5-HT1A gene. Am J Med Genet 60:393–399
Evans DL, Charney DS (2003) Mood disorders and medical illness: a major public health problem. Biol Psychiatry 54:177–180
Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF (1999) Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism. Mol Psychiatry 4:93–96
Frazer A, Hensler JG (1990) 5-HT1A receptors and 5-HT1A-mediated responses: effect on treatments that modify serotonergic neurotransmission. In: Whitaker-Azmitia PM, Peroutka SJ (eds) The neuropharmacology of serotonin. The New York Academy of Sciences, New York, pp 460–475
Gaspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4:1002–1012
Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S (2003) [11C]-DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter: PET characterization and evaluation in cats. Synapse 47:123–133
Gold PW, Gabry KE, Yasuda MR, Chrousos GP (2002) Divergent endocrine abnormalities in melancholic and atypical depression: clinical and pathophysiologic implications. Endocrinol Metab Clin N Am 31:37–62, vi
Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 88:83–87
Greenberg BD, Li Q, Lucas FR et al. (2000) Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet 96:202–216
Groenink L, Pattij T, De Jongh R et al. (2003a) 5-HT1A receptor knockout mice and mice overexpressing corticotropin-releasing hormone in models of anxiety. Eur J Pharmacol 463:185–197
Groenink L, van Bogaert MJ, van der Gugten J, Oosting RS, Olivier B (2003b) 5-HT1A receptor and 5-HT1B receptor knockout mice in stress and anxiety paradigms. Behav Pharmacol 14:369–383
Gross C, Zhuang X, Start K et al. (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behavior in the adult. Nature 416:396–400
Guttmacher AE, Collins FS (2002) Genomic medicine—a primer. N Engl J Med 347:1512–1520
Hariri AR, Mattay VS, Tessitore A et al. (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–403
He M, Sibille E, Benjamin D, Toth M, Shippenberg T (2001) Differential effects of 5-HT1A receptor deletion upon basal and fluoxetine-evoked 5-HT concentrations as revealed by in vivo microdialysis. Brain Res 902:11–17
Healy D, Leonard BE (1987) Monoamine transport in depression: kinetics and dynamics. J Affect Disord 12:91–103
Heils A, Teufel A, Petri S et al. (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624
Heils A, Mossner R, Lesch KP (1997) The human serotonin transporter gene polymorphism—basic research and clinical implications. J Neural Transm 104:1005–1014
Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49:1023–1039
Heinz A, Jones DW, Mazzanti C et al. (2000) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 47:643–649
Heisler LK, Chu HM, Brennan TJ et al. (1998) Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci USA 95:15049–15054
Hendricks T, Francis N, Fyodorov D, Deneris ES (1999) The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. J Neurosci 19:10348–10356
Hensler JG, Kovachich GB, Frazer A (1991) A quantitative autoradiographic study of serotonin1A receptor regulation. Effect of 5,7-dihydroxytryptamine and antidepressant treatments. Neuropsychopharmacology 4:131–144
Jorm AF, Henderson AS, Jacomb PA et al. (1998) An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms. Mol Psychiatry 3:449–451
Kawanishi Y, Harada S, Tachikawa H et al. (1998) Novel mutations in the promoter and coding region of the human 5-HT1A receptor gene and association analysis in schizophrenia. Am J Med Genet 81:434–439
Kim DK, Lim SW, Lee S et al. (2000) Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 11:215–219
Klaassen T, Riedel WJ, van Someren A, Deutz NE, Honig A, van Praag HM (1999) Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders. Biol Psychiatry 46:489–497
Knobelman DA, Hen R, Blendy JA, Lucki I (2001a) Regional patterns of compensation following genetic deletion of either 5-hydroxytryptamine(1A) or 5-hydroxytryptamine(1B) receptor in the mouse. J Pharmacol Exp Ther 298:1092–1100
Knobelman DA, Hen R, Lucki I (2001b) Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse. J Pharmacol Exp Ther 298:1083–1091
Knott VJ, Howson AL, Perugini M, Ravindran AV, Young SN (1999) The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects. Biol Psychiatry 46:229–238
Lemonde S, Turecki G, Bakish D et al. (2003) Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788–8799
Lesch KP, Balling U, Gross J et al. (1994) Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 95:157–162
Lesch KP, Bengel D, Heils A et al. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531
Li T, Holmes C, Sham PC et al. (1997) Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer’s disease. Neuroreport 8:683–686
Little KY, McLaughlin DP, Zhang L et al. (1998) Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am J Psychiatry 155:207–213
Mah EJ, Cunningham KA (1993) Electrophysiological studies of serotnergic (5-HT) modulation of glutamate-evoked activity in amygdala neurons. Soc Neurosci Abstr 19:1554
Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28:1562–1571
Malhotra AK, Goldman D, Mazzanti C, Clifton A, Breier A, Pickar D (1998) A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics. Mol Psychiatry 3:328–332
Malison RT, Price LH, Berman R et al. (1998) Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 44:1090–1098
Manji HK, Drevets WC, Charney DS (2001) The cellular neurobiology of depression. Nat Med 7:541–547
Manji HK, Quiroz JA, Sporn J et al. (2003) Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 53:707–742
Mann JJ, McBride PA, Malone KM, DeMeo M, Keilp J (1995) Blunted serotonergic responsivity in depressed inpatients. Neuropsychopharmacology 13:53–64
Mann JJ, Huang YY, Underwood MD et al. (2000) A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 57:729–738
Mazzanti CM, Lappalainen J, Long JC et al. (1998) Role of the serotonin transporter promoter polymorphism in anxiety- related traits. Arch Gen Psychiatry 55:936–940
McDougle CJ, Epperson CN, Price LH, Gelernter J (1998) Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry 3:270–273
Meijer OC, de Kloet ER (1994) Corticosterone suppresses the expression of 5-HT1A receptor mRNA in rat dentate gyrus. Eur J Pharmacol 266:255–261
Meijer OC, de Kloet ER (1995) A role for the mineralocorticoid receptor in a rapid and transient suppression of hippocampal 5-HT1A receptor mRNA by corticosterone. J Neuroendocrinol 7:653–657
Meijer OC, Van Oosten RV, De Kloet ER (1997) Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine(1A) receptor expression in adrenally intact rats: implication for the pathogenesis of depression. Neuroscience 80:419–426
Meltzer HY, Maes M (1995) Effects of ipsapirone on plasma cortisol and body temperature in major depression. Biol Psychiatry 38:450–457
Mendelson SD, McEwen BS (1991) Autoradiographic analyses of the effects of restraint-induced stress on 5-HT1A, 5-HT1C and 5-HT2 receptors in the dorsal hippocampus of male and female rats. Neuroendocrinology 54:454–461
Mendelson SD, McEwen BS (1992) Autoradiographic analyses of the effects of adrenalectomy and corticosterone on 5-HT1A and 5-HT1B receptors in the dorsal hippocampus and cortex of the rat. Neuroendocrinology 55:444–450
Meyer JH, Wilson AA, Ginovart N et al. (2001) Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study. Am J Psychiatry 158:1843–1849
Meyer JH, Wilson AA, Sagrati S et al. (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161:826–835
Minov C, Baghai TC, Schule C et al. (2001) Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 303:119–122
Montgomery AJ, Bench CJ, Young AH et al. (2001) PET measurement of the influence of corticosteroids on serotonin-1A receptor number. Biol Psychiatry 50:668–676
Moreno FA, Gelenberg AJ, Heninger GR et al. (1999) Tryptophan depletion and depressive vulnerability. Biol Psychiatry 46:498–505
Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ (2002) The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers. Psychopharmacology 163:42–53
Murphy DL, Uhl GR, Holmes A et al. (2003) Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. Genes Brain Behav 2:350–364
Nakhai B, Nielsen DA, Linnoila M et al. (1995) Two naturally occurring amino acid substitutions in the human 5-HT1A receptor: glycine 22 to serine 22 and isoleucine 28 to valine 28. Biochem Biophys Res Commun 210:530–536
Neumeister A (2003) Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull 37:99–115
Neumeister A, Konstantinidis A, Stastny J et al. (2002) Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. Arch Gen Psychiatry 59:613–620
Neumeister A, Bain E, Nugent AC et al. (2004a) Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci 24:589–591
Neumeister A, Nugent AC, Waldeck T et al. (2004b) Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry (in press)
Oldman A, Walsh A, Salkovskis P, Fairburn CG, Cowen PJ (1995) Biochemical and behavioural effects of acute tryptophan depletion in abstinent bulimic subjects: a pilot study. Psychol Med 25:995–1001
Oliveira JR, Gallindo RM, Maia LG et al. (1998) The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer’s disease. Mol Psychiatry 3:438–441
Ou XM, Jafar-Nejad H, Storring JM, Meng JH, Lemonde S, Albert PR (2000) Novel dual repressor elements for neuronal cell-specific transcription of the rat 5-HT1A receptor gene. J Biol Chem 275:8161–8168
Ou XM, Lemonde S, Jafar-Nejad H et al. (2003) Freud-1: a neuronal calcium-regulated repressor of the 5-HT1A receptor gene. J Neurosci 23:7415–7425
Overstreet DH, Commissaris RC, De La Garza R II, File SE, Knapp DJ, Seiden LS (2003) Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models. Stress 6:101–110
Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295
Palacios J, Pazos A, Hoyer D (1987) Characterisation and mapping of 5-HT1A receptors in animals and in man. In: Dourish C, Ahlenius S, Hutson P (eds) Brain 5-HT1A receptors—behavioural and neurochemical pharmacology, vol 67. Ellis Horwood, Chichester, chapter 6
Parks CL, Shenk T (1996) The serotonin 1a receptor gene contains a TATA-less promoter that responds to MAZ and Sp1. J Biol Chem 271:4417–4430
Parsons LH, Kerr TM, Tecott LH (2001) 5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission. J Neurochem 77:607–617
Pattij T, Hijzen TH, Groenink L et al. (2001) Stress-induced hyperhermia in the 5-HT(1A) receptor knockout mouse is normal. Biol Psychiatry 49:569–674
Pattij T, Groenink L, Hijzen TH et al. (2002a) Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice. Neuropsychopharmacology 27:380–390
Pattij T, Groenink L, Oosting RS et al. (2002b) GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knockout mice on a 129/Sv background. Eur J Pharmacol 447:67–74
Pazos A, Probst A, Palacios JM (1987) Serotonin receptors in the human brain. III. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 21:97–122
Pollock BG, Ferrell RE, Mulsant BH et al. (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23:587–590
Pranzatelli MR (1994) Dissociation of the plasticity of 5-HT1A sites and 5-HT transporter sites. Neurochem Res 19:311–315
Quintin P, Benkelfat C, Launay JM et al. (2001) Clinical and neurochemical effect of acute tryptophan depletion in unaffected relatives of patients with bipolar affective disorder. Biol Psychiatry 50:184–190
Ramamoorthy S, Bauman AL, Moore KR et al. (1993) Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 90:2542–2546
Ramboz S, Oosting R, Amara DA et al. (1998) Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci 95:14476–14481
Rees M, Norton N, Jones I et al. (1997) Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). Mol Psychiatry 2:398–402
Regina MJ, Winter JC, Rabin RA (2003) Characterization of a novel effect of serotonin 5-HT1A and 5-HT2A receptors: increasing cGMP levels in rat frontal cortex. Neuropharmacology 45:1041–1049
Roses AD (2000) Idiosyncratic reactions to drugs: can medicine response profiles provide a dynamic drug surveillance system? Clin Chem Lab Med 38:815–818
Roses AD (2002) Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov 1:541–549
Rotondo A, Mazzanti C, Dell’Osso L et al. (2002) Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am J Psychiatry 159:23–29
Rudisch B, Nemeroff CB (2003) Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 54:227–240
Sander T, Harms H, Lesch KP et al. (1997) Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence. Alcohol Clin Exp Res 21:1356–1359
Sargent PA, Kjaer KH, Bench CJ et al. (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57:174–180
Shioe K, Ichimiya T, Suhara T et al. (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
Sibille E, Pavlides C, Benke D, Toth M (2000) Genetic inactivation of the Serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J Neurosci 20:2758–2765
Siever LJ, Murphy DL, Slater S, de la Vega E, Lipper S (1984) Plasma prolactin changes following fenfluramine in depressed patients compared to controls: an evaluation of central serotonergic responsivity in depression. Life Sci 34:1029–1039
Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M (1998) Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 3:508–511
Smith KA, Fairburn CG, Cowen PJ (1997) Relapse of depression after rapid depletion of tryptophan. Lancet 349:915–919
Sprouse JS, Aghajanian GK (1988) Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons. Neuropharmacology 27:707–715
Spurlock G, Buckland P, O’Donovan M, McGuffin P (1994) Lack of effect of antidepressant drugs on the levels of mRNAs encoding serotonergic receptors, synthetic enzymes and 5HT transporter. Neuropharmacology 33:433–440
Storring JM, Charest A, Cheng P, Albert PR (1999) TATA-driven transcriptional initiation and regulation of the rat serotonin 5-HT1A receptor gene. J Neurochem 72:2238–2247
Suhara T, Takano A, Sudo Y et al. (2003) High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography. Arch Gen Psychiatry 60:386–391
Toth M (2003) 5-HT1A receptor knockout mouse as a genetic model of anxiety. Eur J Pharmacol 463:177–184
Verge D, Daval G, Marcinkiewicz M et al. (1986) Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 6:3474–3482
Voderholzer U, Hornyak M, Thiel B et al. (1998) Impact of experimentally induced serotonin deficiency by tryptophan depletion on sleep EEG in healthy subjects. Neuropsychopharmacology 18:112–124
Weller A, Leguisamo AC, Towns L et al. (2003) Maternal effects in infant and adult phenotypes of 5HT1A and 5HT1B receptor knockout mice. Dev Psychobiol 42:194–205
Welner SA, De Montigny C, Desroches J, Desjardins P, Suranyi-Cadotte BE (1989) Autoradiographic quantification of serotonin1A receptors in rat brain following antidepressant drug treatment. Synapse 4:347–352
Whitaker-Azmitia PM, Azmitia EC (1989) Stimulation of astroglial serotonin receptors produces culture media which regulates growth of serotonergic neurons. Brain Res 497:80–85
Whitaker-Azmitia PM, Murphy R, Azmitia EC (1990) Stimulation of astroglial 5-HT1Areceptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphology. Brain Res 528:155–158
Whitaker-Azmitia PM, Clarke C, Azmitia EC (1993) Localization of 5-HT1A receptors to astroglial cells in adult rats: implications for neuronal-glial interactions and psychoactive drug mechanism of action. Synapse 14:201–205
Willeit M, Stastny J, Pirker W et al. (2001) No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry 50:8–12
World Health Organization (2001) Mental health: new understanding, new hope. World Health Organization, Geneva
Wu S, Comings DE (1999) A common C-1018G polymorphism in the human 5-HT1A receptor gene. Psychiatr Genet 9:105–106
Yatham LN, Liddle PF, Shiah IS et al. (2001) Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study. Br J Psychiatry 178:448–453
Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ (2002) Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 7:1115–1119
Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E (2000) Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 20:105–107
Zhuang X, Gross C, Santarelli L, Compan V, Trillat AC, Hen R (1999) Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharmacology 21:S52–S60
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Neumeister, A., Young, T. & Stastny, J. Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter. Psychopharmacology 174, 512–524 (2004). https://doi.org/10.1007/s00213-004-1950-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-004-1950-3