The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder

Recent research has suggested that serotonin, in addition to dopamine, may be involved in the development of attention deficit hyperactivity disorder (ADHD). Serotonin regulates dopaminergic neurotransmission in some areas of the brain via several 5-HT receptors including 5-HT1B. Animal studies have suggested the involvement of the 5-HT1B receptors in locomotor behaviour. For these reasons, we hypothesized that the 5-HT1B receptor gene may be a good candidate for genetic studies of ADHD. We tested for linkage disequilibrium between the 5-HT1B G861C polymorphism and ADHD in 115 families using the transmission disequilibrium test (TDT). We found evidence for a trend towards excess transmission of the 861G allele (χ2=2.91, P=0.09) that when further analysed for parental allele transmissions exhibited significantly greater paternal transmission of the G allele (χ2=4.80, P=0.03) to the affected child. Although preliminary, results from this study provide additional evidence that serotonin genes may be important risk factors for the development of ADHD.

[1]  R Hen,et al.  Enhanced aggressive behavior in mice lacking 5-HT1B receptor. , 1994, Science.

[2]  M. Nöthen,et al.  Identification of genetic variation in the human serotonin 1D beta receptor gene. , 1994, Biochemical and biophysical research communications.

[3]  M. Nöthen,et al.  Identification of Genetic Variation in the Human Serotonin 1Dβ Receptor Gene , 1994 .

[4]  J. Kennedy,et al.  Genetics of childhood disorders: XXIII. ADHD, Part 7: The serotonin system. , 2001, Journal of the American Academy of Child and Adolescent Psychiatry.

[5]  C. Bradberry,et al.  Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization. , 1996, The Journal of pharmacology and experimental therapeutics.

[6]  J. Kennedy,et al.  New polymorphism for the human serotonin 1D receptor variant (5-HT1D beta) not linked to schizophrenia in five Canadian pedigrees. , 1993, Human heredity.

[7]  Arturas Petronis,et al.  The Analysis of Parental Origin of Alleles May Detect Susceptibility Loci for Complex Disorders , 1999, Human Heredity.

[8]  R. Hen,et al.  Insights into the Neurobiology of Impulsive Behavior from Serotonin Receptor Knockout Mice , 1997, Annals of the New York Academy of Sciences.

[9]  L. Siever,et al.  Serotonergic function in aggressive and nonaggressive boys with attention deficit hyperactivity disorder. , 1994, The American journal of psychiatry.

[10]  R. Tannock,et al.  Deficient inhibitory control in attention deficit hyperactivity disorder , 1995, Journal of abnormal child psychology.

[11]  J. Rapoport,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? , 1992, Archives of general psychiatry.

[12]  L. Siever,et al.  Age-related changes in the association between serotonergic function and aggression in boys with ADHD , 1997, Biological Psychiatry.

[13]  J. Rapoport,et al.  Cerebrospinal fluid monoamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents. , 1990, Archives of general psychiatry.

[14]  E D Levin,et al.  Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. , 1999, Science.

[15]  W. Roberts,et al.  Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD) , 2000, Molecular Psychiatry.

[16]  V. Arango,et al.  Relationship of Psychopathology to the Human Serotonin1B Genotype and Receptor Binding Kinetics in Postmortem Brain Tissue , 1999, Neuropsychopharmacology.

[17]  D. Goldman,et al.  Mapping of the serotonin 5-HT1D beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants. , 1995, American journal of medical genetics.

[18]  D. Curtis,et al.  An extended transmission/disequilibrium test (TDT) for multi‐allele marker loci , 1995, Annals of human genetics.

[19]  I. Lucki,et al.  The spectrum of behaviors influenced by serotonin , 1998, Biological Psychiatry.

[20]  P. Wong,et al.  Regulation of striatal dopamine release through 5‐HT1 and 5‐HT2 receptors , 1999 .

[21]  D. Stoff,et al.  Neuroendocrine responses to challenge with dl-fenfluramine and aggression in disruptive behavior disorders of children and adolescents , 1992, Psychiatry Research.

[22]  G. Fillion,et al.  5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes , 1999, Naunyn-Schmiedeberg's Archives of Pharmacology.

[23]  H. Manji,et al.  A Naturally Occurring Amino Acid Substitution of the Human Serotonin 5‐HT2A Receptor Influences Amplitude and Timing of Intracellular Calcium Mobilization , 1997, Journal of neurochemistry.

[24]  Trevor Sharp,et al.  A review of central 5-HT receptors and their function , 1999, Neuropharmacology.

[25]  Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. , 1999, Behavioral neuroscience.

[26]  J. Rawlins,et al.  Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway , 1996, Neuropharmacology.

[27]  L. Siever,et al.  Serotonin, aggression, and parental psychopathology in children with attention-deficit hyperactivity disorder. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.