Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring

Psychopharmacology (Berl). 2011 Oct;217(3):419-32. doi: 10.1007/s00213-011-2299-z. Epub 2011 Apr 14.

Abstract

Rationale: Fluoxetine (Prozac®) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus.

Objectives: The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats.

Methods: Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored.

Results: Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 μg/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT(1A) agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls.

Conclusions: Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT(1A) receptor signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / chemically induced*
  • Anxiety / psychology
  • Behavior, Animal / drug effects*
  • Brain / drug effects
  • Brain / growth & development
  • Chromatography, High Pressure Liquid
  • Female
  • Fluoxetine / administration & dosage
  • Fluoxetine / adverse effects*
  • Fluoxetine / blood
  • Male
  • Maternal-Fetal Exchange
  • Maze Learning / drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / psychology
  • Rats
  • Rats, Wistar
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / adverse effects*
  • Serotonin Uptake Inhibitors / blood
  • Sexual Behavior, Animal / drug effects
  • Social Behavior
  • Swimming

Substances

  • Serotonin Uptake Inhibitors
  • Fluoxetine