5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants

Neuron. 2010 Jan 14;65(1):40-52. doi: 10.1016/j.neuron.2009.12.003.


Most depressed patients don't respond to their first drug treatment, and the reasons for this treatment resistance remain enigmatic. Human studies implicate a polymorphism in the promoter of the serotonin-1A (5-HT(1A)) receptor gene in increased susceptibility to depression and decreased treatment response. Here we develop a new strategy to manipulate 5-HT(1A) autoreceptors in raphe nuclei without affecting 5-HT(1A) heteroreceptors, generating mice with higher (1A-High) or lower (1A-Low) autoreceptor levels. We show that this robustly affects raphe firing rates, but has no effect on either basal forebrain serotonin levels or conflict-anxiety measures. However, compared to 1A-Low mice, 1A-High mice show a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to antidepressant, modeling patients with the 5-HT(1A) risk allele. Furthermore, reducing 5-HT(1A) autoreceptor levels prior to antidepressant treatment is sufficient to convert nonresponders into responders. These results establish a causal relationship between 5-HT(1A) autoreceptor levels, resilience under stress, and response to antidepressants.

Publication types

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

MeSH terms

  • Animals
  • Antidepressive Agents* / pharmacology
  • Antidepressive Agents* / therapeutic use
  • Autoreceptors / genetics
  • Autoreceptors / metabolism*
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Depressive Disorder / drug therapy
  • Depressive Disorder / physiopathology
  • Fluoxetine* / pharmacology
  • Fluoxetine* / therapeutic use
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Polymorphism, Genetic
  • Raphe Nuclei / cytology
  • Raphe Nuclei / metabolism
  • Receptor, Serotonin, 5-HT1A / genetics
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin / metabolism
  • Stress, Psychological / metabolism*


  • Antidepressive Agents
  • Autoreceptors
  • Fluoxetine
  • Receptor, Serotonin, 5-HT1A
  • Serotonin