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

• DOI: 10.1007/s00213-011-2299-z
• Publication Date: 2011-04-13T01:11:18Z
• Authors: Jocelien D. A. Ol...; A. Vallès; Floor van Heesch; Anthonieke Afrasi...; Janneke J. P. M. ...; Marloes Jonkers; Elke Joan Peeters; Gerdien A. H. Kor...; Jos P. Dederen; Amanda J. Kiliaan; Gerard J. Martens; Dirk Schubert; Judith R. Homberg
• Keywords: Male; Behavior, Animal; DCN 2: Functional Neurogenomics; Brain; Anxiety; Rats; 3. Good health; Sexual Behavior, Animal; 03 medical and health sciences; 0302 clinical medicine; Pregnancy; Fluoxetine; Prenatal Exposure Delayed Effects; Animals; Female; Rats, Wistar; Maze Learning; Social Behavior; Maternal-Fetal Exchange; Chromatography, High Pressure Liquid; Selective Serotonin Reuptake Inhibitors; Swimming

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