Does Serotonin Deficit Mediate Susceptibility to ADHD?

Neurochem Int. 2015 Mar;82:52-68. doi: 10.1016/j.neuint.2015.02.001. Epub 2015 Feb 12.


The onset of attention-deficit-hyperactivity-disorder (ADHD) in childhood is characterized by developmentally inappropriate levels of hyperactivity, impulsivity and inattention. A chronic deficit of serotonin (5-HT) at the synapse may trigger symptoms of ADHD. This review focuses on neuro-anatomical, experimental and clinical pharmacological evidence, as well as the genetic underpinnings of serotoninergic involvement in the etiology of ADHD. Neuro-anatomical investigations suggest that serotonin through the orbitofrontal-striatal circuitry may regulate behavioral domains of hyperactivity and impulsivity in ADHD. Studies from animal models of ADHD indicate intimate interplay between 5-HT and dopaminergic neurotransmission. Selective serotonin re-uptake inhibitors, as also non-stimulant drugs acting on the 5-HT system are, however, clinically effective. They impart less severe side effects in patients with no risk of addiction. Oral administration of l-tryptophan, the amino acid precursor of 5-HT, significantly alleviates ADHD symptoms. Given the multifactorial nature of ADHD, candidate gene and genome-wide association studies have suggested that serotoninergic gene variants are associated with increased risk of ADHD with each locus individually exerting a modest effect on overall risk.

Keywords: ADHD; Animal model; Clinical pharmacology; Genetics; Neuroanatomy; Serotonin.

Publication types

  • Review

MeSH terms

  • Adolescent
  • Animals
  • Animals, Newborn
  • Attention Deficit Disorder with Hyperactivity / drug therapy
  • Attention Deficit Disorder with Hyperactivity / genetics*
  • Attention Deficit Disorder with Hyperactivity / physiopathology
  • Central Nervous System Stimulants / therapeutic use
  • Child
  • Child, Preschool
  • Corpus Striatum / physiopathology
  • Disease Models, Animal
  • Dopamine / physiology
  • Gene-Environment Interaction
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Inhibition, Psychological
  • Mice, Knockout
  • Multifactorial Inheritance
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Neurotransmitter Transport Proteins / deficiency
  • Neurotransmitter Transport Proteins / genetics
  • Oxidopamine / toxicity
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Receptor, Serotonin, 5-HT1B / deficiency
  • Serotonin / deficiency*
  • Serotonin / physiology
  • Serotonin Uptake Inhibitors / pharmacology
  • Serotonin Uptake Inhibitors / therapeutic use
  • Tryptophan / deficiency
  • Tryptophan / therapeutic use


  • Central Nervous System Stimulants
  • Nerve Tissue Proteins
  • Neurotransmitter Transport Proteins
  • Receptor, Serotonin, 5-HT1B
  • Serotonin Uptake Inhibitors
  • Serotonin
  • Tryptophan
  • Oxidopamine
  • Dopamine