Postnatal fluoxetine-evoked anxiety is prevented by concomitant 5-HT2A/C receptor blockade and mimicked by postnatal 5-HT2A/C receptor stimulation

Biol Psychiatry. 2014 Dec 1;76(11):858-68. doi: 10.1016/j.biopsych.2013.11.005. Epub 2013 Nov 11.


Background: Postnatal treatment with the selective serotonin reuptake inhibitor fluoxetine, evokes anxiety and depressive behavior in rodent models in adulthood. We examined the role of serotonin 2A (5-HT2A), serotonin 2C (5-HT2C) and serotonin 1A (5-HT1A) receptors, implicated in the development of anxiety, in the behavioral consequences of postnatal fluoxetine (PNFlx).

Methods: Control and PNFlx rat pups received concomitant treatment with the 5-HT2A/C receptor antagonist, ketanserin, the 5-HT2A receptor antagonist, MDL100907, the 5-HT2C receptor antagonist, SB242084, or the 5-HT1A receptor antagonist, WAY-100635, and were tested for behavior in adulthood. The effect of postnatal treatment with the 5-HT2A/C receptor agonist, DOI, on anxiety behavior was examined in adulthood.

Results: Postnatal 5-HT2A/C receptor blockade prevented PNFlx-evoked anxiety, attenuated depressive behavior, and normalized specific gene expression changes in the prefrontal cortex. Postnatal, selective 5-HT2A receptor antagonist treatment blocked PNFlx-evoked anxiety and depressive behavior, whereas 5-HT2C receptor antagonist treatment prevented anxiety but not depressive behavior. Postnatal 5-HT2A/C receptor stimulation was sufficient to evoke anxiety in adulthood. Serotonin 1A receptor blockade did not alter PNFlx-evoked anxiety but resulted in anxiety in control animals, an effect attenuated by concomitant 5-HT2A/C receptor blockade.

Conclusions: Postnatal fluoxetine-evoked anxiety and depressive behavior, as well as specific gene expression changes in the prefrontal cortex, were prevented by 5-HT2A/C receptor blockade. Adult anxiety was evoked by either 5-HT2A/C receptor stimulation or 5-HT1A receptor blockade of naive control pups. Our findings implicate serotonin 2 receptors in the development of perturbed emotionality following PNFlx and suggest that an altered balance of signaling through 5-HT1A and 5-HT2A/C receptors in early life influences anxiety behavior.

Keywords: 5-HT(1A); 5-HT(2A); 5-HT(2C); Antidepressant; DOI; Prozac; SSRI; WAY-100635; ketanserin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / chemically induced
  • Anxiety / physiopathology*
  • Depression / chemically induced
  • Depression / physiopathology
  • Fluoxetine / toxicity
  • Gene Expression
  • Male
  • Motor Activity
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptor, Serotonin, 5-HT1A / physiology
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Receptor, Serotonin, 5-HT2A / physiology*
  • Receptor, Serotonin, 5-HT2C / metabolism
  • Receptor, Serotonin, 5-HT2C / physiology*
  • Selective Serotonin Reuptake Inhibitors / toxicity
  • Serotonin 5-HT2 Receptor Agonists / pharmacology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology


  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Receptor, Serotonin, 5-HT1A