Perinatal vs genetic programming of serotonin states associated with anxiety

Neuropsychopharmacology. 2015 May;40(6):1456-70. doi: 10.1038/npp.2014.331. Epub 2014 Dec 19.


Large numbers of women undergo antidepressant treatment during pregnancy; however, long-term consequences for their offspring remain largely unknown. Rodents exposed to serotonin transporter (SERT)-inhibiting antidepressants during development show changes in adult emotion-like behavior. These changes have been equated with behavioral alterations arising from genetic reductions in SERT. Both models are highly relevant to humans yet they vary in their time frames of SERT disruption. We find that anxiety-related behavior and, importantly, underlying serotonin neurotransmission diverge between the two models. In mice, constitutive loss of SERT causes life-long increases in anxiety-related behavior and hyperserotonemia. Conversely, early exposure to the antidepressant escitalopram (ESC; Lexapro) results in decreased anxiety-related behavior beginning in adolescence, which is associated with adult serotonin system hypofunction in the ventral hippocampus. Adult behavioral changes resulting from early fluoxetine (Prozac) exposure were different from those of ESC and, although somewhat similar to SERT deficiency, were not associated with changes in hippocampal serotonin transmission in late adulthood. These findings reveal dissimilarities in adult behavior and neurotransmission arising from developmental exposure to different widely prescribed antidepressants that are not recapitulated by genetic SERT insufficiency. Moreover, they support a pivotal role for serotonergic modulation of anxiety-related behavior.

Publication types

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

MeSH terms

  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Anxiety Disorders / drug therapy
  • Anxiety Disorders / genetics*
  • Anxiety Disorders / metabolism*
  • Brain / drug effects
  • Brain / growth & development*
  • Brain / metabolism*
  • Citalopram / pharmacology
  • Disease Models, Animal
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Female
  • Fluoxetine / pharmacology
  • Male
  • Mice, 129 Strain
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Antidepressive Agents, Second-Generation
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, mouse
  • Fluoxetine
  • Citalopram
  • Receptor, Serotonin, 5-HT1A
  • Serotonin