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© 1994 Oxford University Press

research-article

A Developmental Neurotoxicity Evaluation of the Effects of Prenatal Exposure to Fluoxetine in Rats

CHARLES V. VORHEES1, KAREN D. ACUFF-SMITH, MARY A. SCHILLING, J. EDWARD FISHER, MARY S. MORAN and JUDY BUELKE-SAM*

Division of Basic Research, Children's Hospital Research Foundation, and Department of Pediatrics and Environmental Health, Univercity of Cincinnati Cincinnati Ohio 45229-3039 *Toxicology, Lilly Research Laboratories, Eli Lilly and Company Greenfield, Indiana 46140

Received April 14, 1993; accepted February 14, 1994

Fluoxetine is a widely used serotonin reuptake inhibitor effective in the treatment of depression. This experiment assessed the potential developmental neurotoxicity of fluoxetine. Sprague-Dawley CD rats were treated once per day on Days 7–20 of gestation with 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolved in distilled water. One control group received water by gavage; animals in this group were provided food and water ad libitum. The second control group (PF) also received water by gavage; animals in this group had their food and water restricted by pair-feeding and watering them to the 12 mg/kg fluoxetine group. Litters were culled to 12 after birth and offspring (male/female pairs) were tested neurobehaviorally at three developmental stages (preweaning, juvenile, and adult). At each stage, two pairs per litter received tests of locomotor activity, acoustic startle, and startle after administration of one of two pharmacological challenges (one pair each receiving fluoxetine or apomorphine). Two pairs were also tested for spontaneous alternation, passive avoidance, and complex learning in a water maze. At the highest dose, fluoxetine caused maternal weight loss during pregnancy, reduced litter sizes at birth, and increased neonatal mortality. No effects on long-term growth or survival were seen. Prenatal fluoxetine exposure produced no significant effects on locomotor activity, spontaneous alternation, passive avoidance, or water maze performance. A few scattered interactions involving treatment group were obtained on startle, but no pattern of treatment-related changes was evident. Regional wet and dry brain weights taken at each stage were not affected by prenatal fluoxetine exposure. The data suggest that fluoxetine is not developmentally neurotoxic in the rat.


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