Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice

Nature. 2011 Apr 7;472(7341):95-9. doi: 10.1038/nature09822. Epub 2011 Mar 23.


Although the question of to whom a male directs his mating attempts is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wild-type level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Hydroxytryptophan / metabolism
  • 5-Hydroxytryptophan / pharmacology
  • Animals
  • Brain / metabolism*
  • Brain / physiology
  • Brain Chemistry
  • Estrous Cycle / physiology
  • Female
  • Heterosexuality / physiology
  • Homosexuality, Male / genetics
  • Housing, Animal
  • Male
  • Mating Preference, Animal / physiology*
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Neurons / physiology
  • Odorants / analysis
  • Serotonin / biosynthesis
  • Serotonin / metabolism*
  • Sex Attractants / analysis
  • Sex Characteristics*
  • Smell
  • Tryptophan Hydroxylase / deficiency
  • Tryptophan Hydroxylase / genetics
  • Tryptophan Hydroxylase / metabolism


  • Sex Attractants
  • Serotonin
  • 5-Hydroxytryptophan
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase