Skip to main content
SpringerLink
Log in

Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis

  • Published:
Current Medical Science Aims and scope Submit manuscript

Summary

Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have reported the association between the serotonin receptor family (5-HTR) gene polymorphisms and ADHD, but the results are still controversial. In this study, we conducted a meta-analysis of the association between 5-HTR1B, 5-HTR2A, and 5-HTR2C genetic variants and ADHD. The results showed that the 861G allele of 5-HTR1B SNP rs6296 could significantly increase the risk of ADHD (C)R=1.09, 95% CI: 1.01-1.18); the 5-HTR2C gene rs518147 (OR=1.69, 95% CI: 1.38-2.07) and rs3813929 (OR = 1.57, 95% CI: 1.25-1.97) were all associated with the risk of ADHD. In addition, we also carried on a casecontrol study to explore the relevance between potential candidate genes 5-HTR1A, 5-HTR1E, 5-HTR3A and ADHD. The results indicated that 5-HTR1A rs6295 genotype (CC+CG vs. GG OR=2.00, 95% CI: 1.23-3.27) and allele (OR=1.77, 95% CI: 1.16-2.72) models were statistically significantly different between case group and control group. This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD, and it also provides more evidence for the etiology of ADHD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kooij SJ, Bejerot S, Blackwell A, et al. European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry, 2010,10:67

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lange KW, Reichl S, Lange KM, et al. The history of attention deficit hyperactivity disorder. Atten Defic Hyperact Disord, 2010,2(4):241–255

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sroubek A, Kelly M, Li X. Inattentiveness in attention-deficit/hyperactivity disorder. Neurosci Bull, 2013,29(1):103–110

    Article  PubMed  PubMed Central  Google Scholar 

  4. Clauss-Ehlers, Caroline S. Encyclopedia of Cross-Cultural School Psychology Springer Science & Business Media. 2010.

    Book  Google Scholar 

  5. Childress AC, Berry SA. Pharmacotherapy of attention-deficit hyperactivity disorder in adolescents. Drugs, 2012,72(3):309–325

    Article  PubMed  CAS  Google Scholar 

  6. Kenemans JL, Bekker EM, Lijffijt M, et al. Attention deficit and impulsivity: selecting, shifting, and stopping. Int J Psychophysiol, 2005,58(1):59–70

    Article  PubMed  CAS  Google Scholar 

  7. Polanczyk G, De Lima MS, Horta BL, et al. The worldwide prevalence of ADHD:a systematic review and metaregression analysis. Am J Psychiatry, 2007,164(6):942–948

    Article  PubMed  Google Scholar 

  8. Akutagava-Martins GC, Salatino-Oliveira A, Kieling CC, et al. Genetics of attention-deficit/hyperactivity disorder: current findings and future directions. Expert Rev Neurother, 2013,13(4):435–445

    Article  PubMed  CAS  Google Scholar 

  9. Baumgaertel A, Wolraich ML, Dietrich M. Comparison of diagnostic criteria for attention deficit disorders in a German elementary school sample. J Am Acad Child Adolesc Psychiatry, 1995,34(5):629–638

    Article  PubMed  CAS  Google Scholar 

  10. Anderson JC, Williams S, McGee R, et al. DSM-III disorders in preadolescent children. Prevalence in a large sample from the general population. Arch Gen Psychiatry, 1987,44(1):69–76

    CAS  Google Scholar 

  11. Biederman J, Faraone SV, Monuteaux MC, et al. Gender effects on attention-deficit/hyperactivity disorder in adults, revisited. Biol Psychiatry, 2004,55(7):692–700

    Article  PubMed  Google Scholar 

  12. Simon V, Czobor P, Bálint S, et al. Prevalence and correlates of adult attention-deficit hyperactivity disorder: Meta-analysis. Br J Psychiatry, 2009,194(3):204–211

    Article  PubMed  Google Scholar 

  13. Shen YC, Wang YF, Yang XL. An epidemiological investigation of minimal brain dysfunction in six elementary schools in Beijing. J Child Psychol Psychiatry, 1985,26(5):777–787

    Article  PubMed  CAS  Google Scholar 

  14. Gao Q, Liu L, Qian Q, et al. Advances in molecular genetic studies of attention deficit hyperactivity disorder in China. Shanghai Arch Psychiatry, 2014,26(4): 194–206

    PubMed  PubMed Central  Google Scholar 

  15. Mannuzza S, Klein RG, Bessler A, et al. Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry, 1993,50(7):565–576

    PubMed  CAS  Google Scholar 

  16. Swanson JM, Sergeant JA, Taylor E, et al. Attentiondeficit hyperactivity disorder and hyperkinetic disorder. Lancet, 1998,351(9100):429–433

    Article  PubMed  CAS  Google Scholar 

  17. Woodward L, Taylor E, Dowdney L. The parenting and family functioning of children with hyperactivity. J Child Psychol Psychiatry, 1998,39(2):161–169

    Article  PubMed  CAS  Google Scholar 

  18. Greydanus DE, Pratt HD, Patel DR. Attention deficit hyperactivity disorder across the lifespan: the child, adolescent, and adult. Dis Mon, 2007,53(2):70–131

    Article  PubMed  Google Scholar 

  19. Barkley RA. Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. Fourth Edition New York Guilford. 2014.

    Google Scholar 

  20. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry, 1991,148(5):564–577

    Article  PubMed  CAS  Google Scholar 

  21. Bihlar MB, Jokinen J, Bolte S, et al. Attention deficit/hyperactivity disorders with co-existing substance use disorder is characterized by early antisocial behaviour and poor cognitive skills. BMC Psychiatry, 2013,13:336

    Article  Google Scholar 

  22. Loeber R, Dishion T. Early predictors of male delinquency: a review. Psychol Bull, 1983,94(1):68–99

    Article  PubMed  CAS  Google Scholar 

  23. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet, 2005,366(9481):237–248

    Article  PubMed  Google Scholar 

  24. Akutagava-Martins GC, Rohde LA, Hutz MH. Genetics of attention-deficit/hyperactivity disorder: an update. Expert Rev Neurother, 2016,16(2): 145–156

    Article  PubMed  CAS  Google Scholar 

  25. Faraone SV, Mick E. Molecular Genetics of Attention Deficit Hyperactivity Disorder. Psychiatr Clin North Am, 2010,33(1):159–180

    Article  PubMed  PubMed Central  Google Scholar 

  26. Thapar A, Cooper M, Eyre O, et al. What have we learnt about the causes of ADHD? J Child Psychol Psychiatry, 2013,54(1):3–16

    Article  PubMed  PubMed Central  Google Scholar 

  27. Franke B, Faraone SV, Asherson P, et al. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatr, 2011,17(10):960–987

    Article  CAS  Google Scholar 

  28. Li Z, Chang S, Zhang L, et al. Molecular genetic studies of ADHD and its candidate genes: A review. Psychiat Res, 2014,219(1): 10–24

    Article  CAS  Google Scholar 

  29. Cifariello A, Pompili A, Gasbarri A. 5-HT(7) receptors in the modulation of cognitive processes. Behav Brain Res, 2008,195(1):171–179

    Article  PubMed  CAS  Google Scholar 

  30. Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry, 1998,44(3):151–162

    Article  PubMed  CAS  Google Scholar 

  31. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology, 1999,38(8): 1083–1152

    Article  PubMed  CAS  Google Scholar 

  32. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav, 2002,71(4):533–554

    Article  PubMed  CAS  Google Scholar 

  33. Nichols DE, Nichols CD. Serotonin receptors. Chem Rev, 2008,108(5): 1614–1641

    Article  PubMed  CAS  Google Scholar 

  34. Filip M, Bader M. Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system. Pharmacol Rep, 2009,61(5):761–777

    Article  PubMed  CAS  Google Scholar 

  35. Advances in Serotonin Receptor Research: Molecular Biology, Signal Transduction, and Therapeutics. Conference proceedings. San Francisco, California, USA. October 8–10, 1997. Ann N Y Acad Sci, 1998,861:1-297

  36. Millan MJ, Marin P, Bockaert J, et al. Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci, 2008,29(9):454–464

    Article  PubMed  CAS  Google Scholar 

  37. Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res, 2008,195(1):198–213

    Article  PubMed  CAS  Google Scholar 

  38. Lanfumey L, Hamon M. 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord, 2004,3(1):1–10

    Article  PubMed  CAS  Google Scholar 

  39. Derks EM, Hudziak JJ, Dolan CV, et al. Genetic and environmental influences on the relation between attention problems and attention deficit hyperactivity disorder. Behav Genet, 2008,38(1):11–23

    Article  PubMed  Google Scholar 

  40. Li J, Wang Y, Zhou R, et al. Serotonin 5-HT IB receptor gene and attention deficit hyperactivity disorder in Chinese Han subjects. Am J Med Genet B Neuropsychiatr Genet, 2005,132B(1):59–63

    Article  PubMed  Google Scholar 

  41. Schmidt LA, Fox NA, Hamer DH. Evidence for a gene-gene interaction in predicting children's behavior problems: association of serotonin transporter short and dopamine receptor D4 long genotypes with internalizing and externalizing behaviors in typically developing 7-year-olds. Dev Psychopathol, 2007,19(4): 1105–1116

    Article  PubMed  Google Scholar 

  42. Stadler C, Schmeck K, Nowraty I, et al. Platelet 5-HT uptake in boys with conduct disorder.. Neuropsychobiology, 2004,50(3):244–251

    Article  PubMed  CAS  Google Scholar 

  43. Van Goozen SH, Fairchild G. Neuroendocrine and neurotransmitter correlates in children with antisocial behavior. Horm Behav, 2006,50(4):647–654

    Article  PubMed  CAS  Google Scholar 

  44. Walstab J, Rappold G, Niesler B. 5-HT(3) receptors: role in disease and target of drugs. Pharmacol Ther, 2010,128(1): 146–169

    Article  PubMed  CAS  Google Scholar 

  45. Walstab J, Hammer C, Lasitschka F, et al. RIC-3 exclusively enhances the surface expression of human homomeric 5-hydroxytryptamine type 3A (5-HT3A) receptors despite direct interactions with 5-HT3A, -C, -D, and -E subunits. J Biol Chem, 2010,285(35):26956–26965

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet, 2009,126(1):51–90

    Article  PubMed  CAS  Google Scholar 

  47. Hoyer D, Clarke DE, Fozard JR, et al. VII International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin). 1994.

    Google Scholar 

  48. Puig MV, Celada P, Artigas F. Serotonergic control of prefrontal cortex. Rev Neurol (Spanish), 2004,39(6):539–547

    CAS  Google Scholar 

  49. Cryan JF, Leonard BE. 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Hum Psychopharmacol, 2000,15(2): 113–135

    Article  PubMed  CAS  Google Scholar 

  50. Evenden JL. The pharmacology of impulsive behaviour in rats VII: the effects of serotonergic agonists and antagonists on responding under a discrimination task using unreliable visual stimuli.. Psychopharmacology, 1999,146(4):422–431

    Article  PubMed  CAS  Google Scholar 

  51. de Boer SF, Koolhaas JM. 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.. Eur J Pharmacol, 2005,526(1-3): 125–139

    Article  PubMed  CAS  Google Scholar 

  52. Hughes ZA, Starr KR, Scott CM, et al. Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B. Psychopharmacology (Berl), 2007,192(1):121–133

    Article  CAS  Google Scholar 

  53. Tsuchida R, Kubo M, Shintani N, et al. Inhibitory effects of osemozotan, a serotonin lA-receptor agonist, on methamphetamine-induced c-Fos expression in prefrontal cortical neurons.. Biol Pharm Bull, 2009,32(4):728–731

    Article  PubMed  CAS  Google Scholar 

  54. Wu S, Comings DE. A common C-1018G polymorphism in the human 5-HT1A receptor gene.. Psychiat Genet, 1999,9(2):105–106

    Article  CAS  Google Scholar 

  55. Czesak M, Lemonde S, Peterson EA, et al. Cellspecific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism. J Neurosci, 2006,26(6): 1864–1871

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Albert PR. Transcriptional regulation of the 5-HT1A receptor: implications for mental illness. Philosophical Transactions of the Royal Society B: Biological Sciences, 2012,367(1601):2402–2415

    Article  CAS  Google Scholar 

  57. Donaldson ZR, le Francois B, Santos TL, et al. The functional serotonin la receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription. Transl Psychiat, 2016,6(3):e746

    Article  CAS  Google Scholar 

  58. Le Francois B, Czesak M, Steubl D, et al. Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology, 2008,55(6):977–985

    Article  PubMed  CAS  Google Scholar 

  59. Shim S, Hwangbo Y, Kwon Y, et al. A case-control association study of serotonin 1A receptor gene and tryptophan hydroxylase 2 gene in attention deficit hyperactivity disorder. Prog Neuro-Psychoph, 2010,34(6):974–979

    Article  CAS  Google Scholar 

  60. Hsu C, Tzang R, Liou Y, et al. Family-based association study of tryptophan hydroxylase 2 and serotonin 1A receptor genes in attention deficit hyperactivity disorder. Psychiat Genet, 2013,23(1):38

    Article  Google Scholar 

  61. Park YH, Lee KK, Kwon HJ, et al. Association between HTR1A gene polymorphisms and attention deficit hyperactivity disorder in Korean children. Genet Test Mol Bioma, 2013,17(3):178–182

    Article  CAS  Google Scholar 

  62. Hawi Z, Dring M, Kirley A, et al. Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(lB) receptor gene in 273 nuclear families from a multicentre sample. Mol Psychiatry, 2002,7(7):718–725

    Article  PubMed  CAS  Google Scholar 

  63. Quist JF, Kennedy JL. Genetics of childhood disorders: XXIII. ADHD, Part 7: The serotonin systemJ Am Acad Child Psy, 2001,40(2):253–256

    CAS  Google Scholar 

  64. Clark MS, Neumaier JF. The 5-HT1B receptor: behavioral implications. Psychopharmacol Bull, 2001,35(4): 170–185

    PubMed  CAS  Google Scholar 

  65. Brunner D, Buhot MC, Hen R, et al. Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. Behav Neurosci, 1999,113(3):587–601

    Article  PubMed  CAS  Google Scholar 

  66. Ramboz S, Saudou F, Amara DA, et al. 5-HT1B receptor knock out—behavioral consequences. Behav Brain Res, 1996,73(l-2):305–312

    PubMed  CAS  Google Scholar 

  67. Saudou F, Amara DA, Dierich A, et al. Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science, 1994,265(5180): 1875–1878

    Article  PubMed  CAS  Google Scholar 

  68. Dulawa SC, Hen R, Scearce-Levie K, et al. SerotoninlB receptor modulation of startle reactivity, habituation, and prepulse inhibition in wild-type and serotoninlB knockout mice. Psychopharmacology (Berl), 1997,132(2): 125–134

    Article  CAS  Google Scholar 

  69. Barot SK, Ferguson SM, Neumaier JF. 5-HT(lB) receptors in nucleus accumbens efferents enhance both rewarding and aversive effects of cocaine. Eur J Neurosci, 2007,25(10):3125–3131

    Article  PubMed  Google Scholar 

  70. Borycz J, Zapata A, Quiroz C, et al. 5-HT1B receptor-mediated serotoninergic modulation of methylphenidate-induced locomotor activation in rats. Neuropsychopharmacol, 2008,33(3):619–626

    Article  CAS  Google Scholar 

  71. Hall FS, Sora I, Hen R, et al. Serotonin/Dopamine Interactions in a Hyperactive Mouse: Reduced Serotonin Receptor IB Activity Reverses Effects of Dopamine Transporter Knockout. PLoS One, 2014,9(12):e115009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Huang YY, Grailhe R, Arango V, et al. Relationship of psychopathology to the human serotoninlB genotype and receptor binding kinetics in postmortem brain tissue. Neuropsychopharmacol, 1999,21(2):238–246

    Article  CAS  Google Scholar 

  73. Quist JF, Barr CL, Schachar R, et al. The serotonin 5-HT IB receptor gene and attention deficit hyperactivity disorder. Mol Psychiatry, 2003,8(1):98–102

    Article  PubMed  CAS  Google Scholar 

  74. Hawi Z, Segurado R, Conroy J, et al. Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder. Am J Hum Genet, 2005,77(6):958–965

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Smoller JW, Biederman J, Arbeitman L, et al. Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD. Biol Psychiatry, 2006,59(5):460–467

    Article  PubMed  CAS  Google Scholar 

  76. Guimaraes AP, Schmitz M, Polanczyk GV, et al. Further evidence for the association between attention deficit/hyperactivity disorder and the serotonin receptor IB gene. J Neural Transm, 2009,116(12): 1675–1680

    Article  PubMed  CAS  Google Scholar 

  77. Baneijee E, Baneijee D, Chatteijee A, et al. Selective matemal inheritance of risk alleles and genetic interaction between serotonin receptor-IB (5-HTR1B) and serotonin transporter (SLC6A4) in ADHD. Psychiatry Res, 2012,200(2-3):1083–1085

    Article  CAS  Google Scholar 

  78. Fonseca DJ, Mateus HE, Galvez JM, et al. Lack of association of polymorphisms in six candidate genes in Colombian adhd patients. Ann Neurosci, 2015,22(4):217–221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Oades RD. Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). Prog Brain Res, 2008,172:543–565

    Article  PubMed  CAS  Google Scholar 

  80. Cote F, Fligny C, Bayard E, et al. Matemal serotonin is crucial for murine embryonic development. P Natl Acad Sei Usa, 2007,104(1):329–334

    Article  CAS  Google Scholar 

  81. Ogdie MN, Fisher SE, Yang M, et al. Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p 13, 6ql2,16pl3, and 17pll. Am JHum Genet, 2004,75(4):661–668

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Brookes K, Xu X, Chen W, et al. The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry, 2006,11(10):934–953

    Article  PubMed  CAS  Google Scholar 

  83. Lasky-Su J, Neale BM, Franke B, et al. Genomewide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet, 2008,147B(8): 1345–1354

    Article  PubMed  CAS  Google Scholar 

  84. Oades RD, Lasky-Su J, Christiansen H, et al. The influence of serotonin-and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behav Brain Funct, 2008,4:48

    Article  PubMed  PubMed Central  Google Scholar 

  85. Lesch KP, Waider J. Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron, 2012,76(1):175–191

    Article  PubMed  CAS  Google Scholar 

  86. Hartig PR, Branchek TA, Weinshank RL. A subfamily of 5-HT1D receptor genes. Trends Pharmacol Sei, 1992,13(4): 152–159

    Article  CAS  Google Scholar 

  87. Li J, Zhang X, Wang Y, et al. The serotonin 5-HT1D receptor gene and attention-deficit hyperactivity disorder in Chinese Han subjects. Am J Med Genet B Neuropsychiatr Genet, 2006,141B(8):874–876

    Article  PubMed  CAS  Google Scholar 

  88. Sparkes RS, Lan N, Klisak I, et al. Assignment of a serotonin 5HT-2 receptor gene (HTR2) to human chromosome 13ql4-q21 and mouse chromosome 14. Genomics, 1991,9(3):461–465

    Article  PubMed  CAS  Google Scholar 

  89. Rosel P, Arranz B, Urretavizcaya M, et al. Different distributions of the 5-HT reuptake complex and the postsynaptic 5-HT(2A) receptors in Brodmann areas and brain hemispheres. Psychiatry Res, 2002,111(2-3):105–115

    Article  PubMed  CAS  Google Scholar 

  90. O'Neill MF, Heron-Maxwell CL, Shaw G. 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB. Pharmacol Biochem Behav, 1999,63(2):237–243

    Article  PubMed  CAS  Google Scholar 

  91. Cho SC, Son JW, Kim BN, et al. Serotonin 2A Receptor Gene Polymorphism in Korean Children with Attention-Deficit/Hyperactivity Disorder. Psychiatry Investig, 2012,9(3):269–277

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and realworld psychiatric practice. J Clin Psychiatry, 2003,64 Suppl 19:6–12

    PubMed  Google Scholar 

  93. Erdmann J, Shimron-Abarbanell D, Rietschel M, et al. Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet, 1996,97(5):614–619

    Article  PubMed  CAS  Google Scholar 

  94. Hazelwood LA, Sanders-Bush E. His452Tyr polymorphism in the human 5-HT2A receptor destabilizes the signaling conformation. Mol Pharmacol, 2004,66(5): 1293–1300

    PubMed  CAS  Google Scholar 

  95. Ozaki N, Manji H, Lubierman V, et al. A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization. J Neurochem, 1997,68(5):2186–2193

    Article  PubMed  CAS  Google Scholar 

  96. Quist JF, Barr CL, Schachar R, et al. Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD). Mol Psychiatry, 2000,5(5):537–541

    Article  PubMed  CAS  Google Scholar 

  97. Bobb AJ, Addington AM, Sidransky E, et al. Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet, 2005,134B(1):67–72

    Article  PubMed  Google Scholar 

  98. Guimaraes AP, Zeni C, Polanczyk GV, et al. Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: preferential transmission of the HTR2A 452His allele to affected boys. Am J Med Genet B Neuropsychiatr Genet, 2007,144B(1):69–73

    Article  PubMed  CAS  Google Scholar 

  99. Heiser P, Dempfle A, Friedel S, et al. Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample. J Neural Transm, 2007,114(4):513–521

    Article  PubMed  CAS  Google Scholar 

  100. Elia J, Capasso M, Zaheer Z, et al. Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: suggestive association signals in ADRA1 A. Psychiatr Genet, 2009,19(3):134–141

    Article  PubMed  Google Scholar 

  101. Turecki G, Briere R, Dewar K, et al. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry, 1999,156(9): 1456–1458

    PubMed  CAS  Google Scholar 

  102. Brown GL, Linnoila MI. CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. J Clin Psychiatry, 1990,51(Suppl):31-41, 42–43

    Google Scholar 

  103. Li J, Wang Y, Zhou R, et al. No association of attention-deficit/hyperactivity disorder with genes of the serotonergic pathway in Han Chinese subjects. Neurosci Lett, 2006,403(1-2):172–175

    Article  PubMed  CAS  Google Scholar 

  104. Zoroglu SS, Erdal ME, Erdal N, et al. No evidence for an association between the T102C and 1438 G/A polymorphisms of the serotonin 2A receptor gene in attention deficit/hyperactivity disorder in a Turkish population. Neuropsychobiology, 2003,47(1):17–20

    Article  PubMed  CAS  Google Scholar 

  105. Li J, Kang C, Wang Y, et al. Contribution of 5-HT2A receptor gene -1438A>G polymorphism to outcome of attention-deficit/hyperactivity disorder in adolescents. Am J Med Genet B Neuropsychiatr Genet, 2006,141B(5):473–476

    Article  PubMed  CAS  Google Scholar 

  106. Li J, Wang Y, Qian Q, et al. Association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder in children. Zhonghua Yi Xue Za Zhi (Chinese), 2002,82(17):1173–1176

    CAS  Google Scholar 

  107. Reuter M, Kirsch P, Hennig J. Inferring candidate genes for attention deficit hyperactivity disorder (ADHD) assessed by the World Health Organization Adult ADHD Self-Report Scale (ASRS). J Neural Transm, 2006,113(7):929–938

    Article  PubMed  CAS  Google Scholar 

  108. Arranz MJ, Munro J, Owen MJ, et al. Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry, 1998,3(1):61–66

    Article  PubMed  CAS  Google Scholar 

  109. Arranz MJ, Collier DA, Munro J, et al. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett, 1996,217(2-3): 177–178

    Article  PubMed  CAS  Google Scholar 

  110. Pazvantoglu O, Gunes S, Karabekiroglu K, et al. The relationship between the presence of ADHD and certain candidate gene polymorphisms in a Turkish sample. Gene, 2013,528(2):320–327

    Article  PubMed  CAS  Google Scholar 

  111. Baneijee E, Nandagopal K. Does serotonin deficit mediate susceptibility to ADHD?. Neurochem Int, 2015,82:52–68

    Article  CAS  Google Scholar 

  112. Berg KA, Clarke WP, Cunningham KA, et al. Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology, 2008,55(6):969–976

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Leysen JE. 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord, 2004,3(1):11–26

    Article  PubMed  CAS  Google Scholar 

  114. Baxter G, Kennett G, Blaney F, et al. 5-HT2 receptor subtypes: a family re-united?. Trends Pharmacol Sci, 1995,16(3):105–110

    Article  PubMed  CAS  Google Scholar 

  115. Milatovich A, Hsieh CL, Bonaminio G, et al. Serotonin receptor 1 c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). Hum Mol Genet, 1992,1(9):681–684

    Article  PubMed  CAS  Google Scholar 

  116. Serrats J, Mengod G, Cortes R. Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei. J Chem Neuroanat, 2005,29(2):83–91

    Article  PubMed  CAS  Google Scholar 

  117. Oades RD. Function and dysfunction of monoamine interactions in children and adolescents with AD/HD. EXS, 2006,98:207–244

    PubMed  CAS  Google Scholar 

  118. Lucas G, Spampinato U. Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum. J Neurochem, 2000,74(2):693–701

    Article  PubMed  CAS  Google Scholar 

  119. Stiedl O, Misane I, Koch M, et al. Activation of the brain 5-HT2C receptors causes hypolocomotion without anxiogenic-like cardiovascular adjustments in mice. Neuropharmacology, 2007,52(3):949–957

    Article  PubMed  CAS  Google Scholar 

  120. Robinson ES, Dalley JW, Theobald DE, et al. Opposing roles for 5-HT2A and 5-HT2C receptors in the nucleus accumbens on inhibitory response control in the 5-choice serial reaction time task. Neuropsychopharmacol, 2008,33(10):2398–2406

    Article  CAS  Google Scholar 

  121. Pennanen L, van der Hart M, Yu L, et al. Impact of serotonin (5-HT)2C receptors on executive control processes. Neuropsychopharmacol, 2013,38(6):957–967

    Article  CAS  Google Scholar 

  122. Grottick AJ, Corrigall WA, Higgins GA. Activation of 5-HT(2C) receptors reduces the locomotor and rewarding effects of nicotine. Psychopharmacology (Berl), 2001,157(3):292–298

    Article  CAS  Google Scholar 

  123. Johann M, Bobbe G, Putzhammer A, et al. Comorbidity of alcohol dependence with attentiondeficit hyperactivity disorder: differences in phenotype with increased severity of the substance disorder, but not in genotype (serotonin transporter and 5-hydroxytryptamine-2c receptor). Alcohol Clin Exp Res, 2003,27(10):1527–1534

    Article  PubMed  CAS  Google Scholar 

  124. Li J, Wang YF, Zhou RL, et al. Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid with learning disorder. Beijing Da Xue Xue Bao (Chinese), 2004,36(4):366–369

    CAS  Google Scholar 

  125. Li J, Wang Y, Zhou R, et al. Association between polymorphisms in serotonin 2C receptor gene and attention-deficit/hyperactivity disorder in Han Chinese subjects. Neurosci Lett, 2006,407(2): 107–111

    Article  PubMed  CAS  Google Scholar 

  126. Li J, Wang YF, Zhou RL, et al. Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder in children with or without comorbidity of disruptive behavior disorder. Zhonghua Er Ke Za Zhi (Chinese), 2007,45(5):374–377

    CAS  Google Scholar 

  127. Xu X, Brookes K, Sun B, et al. Investigation of the serotonin 2C receptor gene in attention deficit hyperactivity disorder in UK samples. BMC Res Notes, 2009,2:71

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Ribases M, Ramos-Quiroga JA, Hervas A, et al. Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/ hyperactivity disorder identifies association for 5HT2A, DDC and MAOB. Mol Psychiatry, 2009,14(1):71–85

    Article  PubMed  CAS  Google Scholar 

  129. Niesler B, Kapeller J, Hammer C, et al. Serotonin type 3 receptor genes: HTR3A, B, C, D, E. Pharmacogenomics, 2008,9(5):501–504

    Article  PubMed  CAS  Google Scholar 

  130. Engel M, Smidt MP, van Hooft JA. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cell Neurosci, 2013,7:76

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Thompson AJ, Lummis SC. 5-HT3 receptors. Curr Pharm Des, 2006,12(28):3615–3630

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Bockaert J, Claeysen S, Compan V, et al. 5-HT4 receptors. Curr Drug Targets CNS Neurol Disord, 2004,3(1):39–51

    Article  PubMed  CAS  Google Scholar 

  133. Mannuzza S, Klein RG, Konig PH, et al. Hyperactive boys almost grown up. IV. Criminality and its relationship to psychiatric status. Arch Gen Psychiatry, 1989,46(12): 1073–1079

    Article  PubMed  CAS  Google Scholar 

  134. Bonhomme N, De Deurwaerdere P, Le Moal M, et al. Evidence for 5-HT4 receptor subtype involvement in the enhancement of striatal dopamine release induced by serotonin: a microdialysis study in the halothane-anesthetized rat. Neuropharmacology, 1995,34(3):269–279

    Article  PubMed  CAS  Google Scholar 

  135. Compan V, Zhou M, Grailhe R, et al. Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice. J Neurosci, 2004,24(2):412–419

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  136. Li J, Wang Y, Zhou R, et al. Association of attentiondeficit/ hyperactivity disorder with serotonin 4 receptor gene polymorphisms in Han Chinese subjects. Neurosci Lett, 2006,401(l-2):6–9

    Article  PubMed  CAS  Google Scholar 

  137. Adriani W, Leo D, Greco D, et al. Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression. Neuropsychopharmacol, 2006,31(9): 1946–1956

    Article  CAS  Google Scholar 

  138. Ruocco LA, Romano E, Treno C, et al. Emotional and risk seeking behavior after prepuberal subchronic or adult acute stimulation of 5-HT7-Rs in Naples High Excitability rats. Synapse, 2014,68(4):159–167

    Article  PubMed  CAS  Google Scholar 

  139. Canese R, Marco EM, De Pasquale F, et al. Differential response to specific 5-Ht(7) versus whole-serotonergic drugs in rat forebrains: a phMRI study. Neuroimage, 2011,58(3):885–894

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Key Laboratory of Environment and Health, Ministry of Education & Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Yu-wei Hou, Xue Gu, Xin Huang, Min Wang & Jing Wu

  2. Department of Rehabilitation, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430015, China

    Ping Xiong

Authors
  1. Yu-wei Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xue Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing Wu.

Additional information

This study was supported by National Natural Science Foundation of China (No. 81773456)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, Yw., Xiong, P., Gu, X. et al. Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis. CURR MED SCI 38, 538–551 (2018). https://doi.org/10.1007/s11596-018-1912-3

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-018-1912-3

Key words

Search

Navigation