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Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo.

The serotonergic system, including the serotonin 1A (5-HT(1A)) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data show substantial interindividual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT(1A) receptor expression. We used positron emission tomography and [(11)C]WAY-100635 to quantify 5-HT(1A) receptors in a group of 31 healthy and unmedicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. ANOVA of 5-HT(1A) receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p < 0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT(1A) receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p < 0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT(1A) receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.

Pubmed ID: 18971477


  • Mickey BJ
  • Ducci F
  • Hodgkinson CA
  • Langenecker SA
  • Goldman D
  • Zubieta JK


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

October 29, 2008

Associated Grants

  • Agency: NCRR NIH HHS, Id: M01 RR000042
  • Agency: NCRR NIH HHS, Id: M01 RR000042-441387
  • Agency: NCRR NIH HHS, Id: M01 RR000042-441440
  • Agency: NIMH NIH HHS, Id: P01 MH042251
  • Agency: NIMH NIH HHS, Id: P01 MH042251-160013
  • Agency: NIMH NIH HHS, Id: P01 MH42251
  • Agency: NIMH NIH HHS, Id: R25 MH6374
  • Agency: NCRR NIH HHS, Id: RR00042
  • Agency: Intramural NIH HHS, Id: Z01 AA000306-02

Mesh Terms

  • Adult
  • Brain Stem
  • Depressive Disorder
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Monoamine Oxidase
  • Polymorphism, Genetic
  • Predictive Value of Tests
  • Prosencephalon
  • Protein Binding
  • Receptor, Serotonin, 5-HT1A
  • Sex Characteristics