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  • Original Research Article
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Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD)

Abstract

A recent study demonstrated that treatment of hyperactive mice with psychostimulants and serotonergic agents produced a calming effect that was dependent on serotonergic neurotransmission and was not associated with any changes in extracellular dopamine levels.1 The complex interaction between the serotonergic and dopaminergic neurotransmitter systems suggests that a balance between the two systems may be necessary for mediating hyperactive behaviour. Defects in serotonin system genes, therefore, may disrupt normal brain serotonin function causing an imbalance between these neurotransmitter systems leading to the development of attention deficit hyperactivity disorder (ADHD). Using the transmission disequilibrium test (TDT), the current study assesses for linkage disequilibrium between polymorphisms in the serotonin HTR2A receptor gene and ADHD. One hundred and fifteen families with a total of 143 children diagnosed with ADHD (DSM-IV) were genotyped for the His452Tyr and the T102C polymorphisms in the serotonin HTR2A receptor gene. TDT analysis revealed a preferential transmission of the 452Tyr allele to the affected offspring (P = 0.03), suggesting linkage disequilibrium of this polymorphism with ADHD. This may open a new door in ADHD molecular genetics research, expanding the existing view of a catecholaminergic hypothesis to include a serotonergic hypothesis and should help elucidate the complex interplay among the neurotransmitter systems in the etiology of ADHD.

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References

  1. Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG . Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity Science 1999; 283: 397–401

    Article  CAS  PubMed  Google Scholar 

  2. American Psychiatric Association . Diagnostic and Statistical Manual of Mental disorders, 4th edn American Psychiatric Association: Washington, DC 1994

    Google Scholar 

  3. Faraone SV, Biederman J . Neurobiology of attention-deficit hyperactivity disorder Biol Psychiatry 1998; 44: 951–958

    Article  CAS  PubMed  Google Scholar 

  4. Kelland MD, Chiodo LA . Serotonergic modulation of midbrain dopamine systems. In: Ashby CR Jr (ed) The Modulation of Dopaminergic Neurotransmission by Other Neurotransmitters CRC Press: Boca Raton, Florida 1996; pp87–122

    Google Scholar 

  5. Bhagavan HN, Coleman M, Coursin DB . The effect of pyridoxine hydrochloride on blood serotonin and pyridoxal phosphate contents in hyperactive children Pediatrics 1975; 55: 437–441

    CAS  PubMed  Google Scholar 

  6. Coleman M . Serotonin concentrations in whole blood of hyperactive children J Pediatr 1971; 78: 985–990

    Article  CAS  PubMed  Google Scholar 

  7. Spivak B, Vered Y, Yoran-Hegesh R, Averbuch E, Mester R, Graf E et al. Circulatory levels of catecholamines, serotonin and lipids in attention deficit hyperactivity disorder Acta Psychiatr Scand 1999; 99: 300–304

    Article  CAS  PubMed  Google Scholar 

  8. Barrickman L, Noyes R, Kuperman S, Schumacher E, Verda M . Treatment of ADHD with fluoxetine: a preliminary trial J Am Acad Child Adolesc Psychiatry 1991; 30: 762–767

    CAS  PubMed  Google Scholar 

  9. Ernst M, Liebenauer LL, Tebeka D, Jons PH, Eisenhofer G, Murphy DL et al. Selegiline in ADHD adults: plasma monoamines and monoamine metabolites Neuropsychopharmacology 1997; 16: 276–284

    Article  CAS  PubMed  Google Scholar 

  10. Kruesi MJ, Rapoport JL, Hamburger S, Hibbs E, Potter WZ, Lenane M et al. Cerebrospinal fluid monoamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents Arch Gen Psychiatry 1990; 47: 419–426

    Article  CAS  PubMed  Google Scholar 

  11. Kruesi MJ, Hibbs ED, Zahn TP, Keysor CS, Hamburger SD, Bartko JJ et al. A 2-year prospective follow-up study of children and adolescents with disruptive behavior disorders. Prediction by cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and autonomic measures? Arch Gen Psychiatry 1992; 49: 429–435

    Article  CAS  PubMed  Google Scholar 

  12. Halperin JM, Sharma V, Siever LJ, Schwartz ST, Matier K, Wornell G et al. Serotonergic function in aggressive and nonaggressive boys with attention deficit hyperactivity disorder Am J Psychiatry 1994; 151: 243–248

    Article  CAS  PubMed  Google Scholar 

  13. Castellanos FX, Elia J, Kruesi MJ, Gulotta CS, Mefford IN, Potter WZ et al. Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder Psychiatry Res 1994; 52: 305–316

    Article  CAS  PubMed  Google Scholar 

  14. Pine DS, Coplan JD, Wasserman GA, Miller LS, Fried JE, Davies M et al. Neuroendocrine response to fenfluramine challenge in boys. Associations with aggressive behavior and adverse rearing [published erratum appears in Arch Gen Psychiatry 1998; 55: 625] Arch Gen Psychiatry 1997; 54: 839–846

    Article  CAS  PubMed  Google Scholar 

  15. Puumala T, Sirvio J . Changes in activities of dopamine and serotonin systems in the frontal cortex underlie poor choice accuracy and impulsivity of rats in an attention task Neuroscience 1998; 83: 489–499

    Article  CAS  PubMed  Google Scholar 

  16. Biederman J, Munir K, Knee D, Habelow W, Armentano M, Autor S et al. A family study of patients with attention deficit disorder and normal controls J Psychiatr Res 1986; 20: 263–274

    Article  CAS  PubMed  Google Scholar 

  17. Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT . Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder J Am Acad Child Adolesc Psychiatry 1990; 29: 526–533

    Article  CAS  PubMed  Google Scholar 

  18. Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C et al. Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples Arch Gen Psychiatry 1992; 49: 728–738

    Article  CAS  PubMed  Google Scholar 

  19. Thapar A, Holmes J, Poulton K, Harrington R . Genetic basis of attention deficit and hyperactivity Br J Psychiatry 1999; 174: 105–111

    Article  CAS  PubMed  Google Scholar 

  20. Hechtman L . Families of children with attention deficit hyperactivity disorder: a review Can J Psychiatry 1996; 41: 350–360

    Article  CAS  PubMed  Google Scholar 

  21. Cook EH, Jr, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE et al. Association of attention-deficit disorder and the dopamine transporter gene Am J Hum Genet 1995; 56: 993–998

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M . Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism Mol Psychiatry 1997; 2: 311–313

    Article  CAS  PubMed  Google Scholar 

  23. Daly G, Hawi Z, Fitzgerald M, Gill M . Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children Mol Psychiatry 1999; 4: 192–196

    Article  CAS  PubMed  Google Scholar 

  24. Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL et al. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity Am J Hum Genet 1998; 63: 1767–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hsieh CL, Bowcock AM, Farrer LA, Hebert JM, Huang KN, Cavalli-Sforza LL et al. The serotonin receptor subtype 2 locus HTR2 is on human chromosome 13 near genes for esterase D and retinoblastoma-1 and on mouse chromosome 14 Somat Cell Mol Genet 1990; 16: 567–574

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. 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: 237–243

    Article  CAS  PubMed  Google Scholar 

  28. Ozaki N, Rosenthal NE, Pesonen U, Lappalainen J, Feldman-Naim S, Schwartz PJ et al. Two naturally occurring amino acid substitutions of the 5-HT2A receptor: similar prevalence in patients with seasonal affective disorder and controls Biol Psychiatry 1996; 40: 1267–1272

    Article  CAS  PubMed  Google Scholar 

  29. Erdmann J, Shimron-Abarbanell D, Rietschel M, Albus M, Maier W, Korner J 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: 614–619

    Article  CAS  PubMed  Google Scholar 

  30. Warren JT, Jr, Peacock ML, Rodriguez LC, Fink JK . An MspI polymorphism in the human serotonin receptor gene (HTR2): detection by DGGE and RFLP analysis Hum Mol Genet 1993; 2: 338

    Article  CAS  PubMed  Google Scholar 

  31. Ozaki N, Manji H, Lubierman V, Lu SJ, Lappalainen J, Rosenthal NE 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: 2186–2193

    Article  CAS  PubMed  Google Scholar 

  32. Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL . 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine Eur J Pharmacol 1992; 223: 65–74

    Article  CAS  PubMed  Google Scholar 

  33. Schmidt CJ, Sullivan CK, Fadayel GM . Blockade of striatal 5-hydroxytryptamine2 receptors reduces the increase in extracellular concentrations of dopamine produced by the amphetamine analogue 3,4-methylenedioxymethamphetamine J Neurochem 1994; 62: 1382–1389

    Article  CAS  PubMed  Google Scholar 

  34. Moser PC, Moran PM, Frank RA, Kehne JH . Reversal of amphetamine-induced behaviours by MDL 100,907, a selective 5-HT2A antagonist Behav Brain Res 1996; 73: 163–167

    Article  CAS  PubMed  Google Scholar 

  35. Kapur S, Remington G . Serotonin-dopamine interaction and its relevance to schizophrenia Am J Psychiatry 1996; 153: 466–476

    Article  CAS  PubMed  Google Scholar 

  36. Conners CK . Conners Rating Scales–Revised Multi-Health Systems Inc: Toronto, Canada 1997

    Google Scholar 

  37. Boyle MH, Offord DR, Racine Y, Fleming JE, Szatmari P, Sanford M . Evaluation of the revised Ontario Child Health Study scales J Child Psychol Psychiatry 1993; 34: 189–213

    Article  CAS  PubMed  Google Scholar 

  38. Reynolds CR, Richmond BO . What I Think and Feel (RCMAS) Western Psychological Services: Los Angeles, CA 1985

    Google Scholar 

  39. Kovacs M . Manual: The Children's Depression Inventory Multi-Health Systems Inc: Toronto, Canada 1995

    Google Scholar 

  40. Wechsler DI . Examiner's Manual: Wechsler Intelligence Scale for Children, 3rd edn Psychological Corporation: New York, NY 1991

    Google Scholar 

  41. Wilkinson GS . Wide Range Achievement test 3—Revision 3 Jastak Associates: Wilmington, DE 1993

    Google Scholar 

  42. Semel E, Wing E, Secord W . Clinical Evaluation of Language Fundamentals–Third Edition (CELF-3) The Psychological Corporation: San Antonio, TX 1995

    Google Scholar 

  43. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res 1988; 16: 1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sham PC, Curtis D . An extended transmission/disequilibrium test (TDT) for multi-allele marker loci Ann Hum Genet 1995; 59: 323–336

    Article  CAS  PubMed  Google Scholar 

  45. Clayton D, Jones H . Transmission/disequilibrium tests for extended marker haplotypes Am J Hum Genet 1999; 65: 1161–1169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Terwilliger J, Ott J . Handbook for Human Genetic Linkage Johns Hopkins University Press: Baltimore 1994

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from The Hospital for Sick Children Psychiatric Endowment Fund, The National Alliance for Research in Schizophrenia and Affective Disorders (CLB and JLK), the Medical Research Council of Canada (MT14336 and PG11121) and the National Humanities Research Development Program No. 6606-5612-401 (RS).

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Correspondence to J L Kennedy.

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Quist, J., Barr, C., Schachar, R. et al. Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD). Mol Psychiatry 5, 537–541 (2000). https://doi.org/10.1038/sj.mp.4000779

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