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

Fluoxetine is a widely used serotonin reuptake inhibitor effectivein the treatment of depression. This experiment assessed thepotential developmental neurotoxicity of fluoxetine. Sprague-DawleyCD rats were treated once per day on Days 7–20 of gestationwith 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolvedin 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 bypair-feeding and watering them to the 12 mg/kg fluoxetine group.Litters were culled to 12 after birth and offspring (male/femalepairs) were tested neurobehaviorally at three developmentalstages (preweaning, juvenile, and adult). At each stage, twopairs per litter received tests of locomotor activity, acousticstartle, and startle after administration of one of two pharmacologicalchallenges (one pair each receiving fluoxetine or apomorphine).Two pairs were also tested for spontaneous alternation, passiveavoidance, and complex learning in a water maze. At the highestdose, 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. Prenatalfluoxetine exposure produced no significant effects on locomotoractivity, spontaneous alternation, passive avoidance, or watermaze performance. A few scattered interactions involving treatmentgroup were obtained on startle, but no pattern of treatment-relatedchanges was evident. Regional wet and dry brain weights takenat each stage were not affected by prenatal fluoxetine exposure.The data suggest that fluoxetine is not developmentally neurotoxicin the rat.     

Postnatal Toxicity following Prenatal Reserpine Exposure in Rats: Effects of Dose and Dosing Schedule

Postnatal Toxicity following Prenatal Reserpine Exposure inRats: Effects of Dose and Dosing Schedule. BUELKE-SAM, J., KIMMEL,G. L., WEBB, P. J., SUKKER, W., JR., NEWPORT, G. D., NELSON,C. J., AND KIMMEL, C. A. (1984). Fundam. Appl. Toxicol. 4, 983–991.Pregnant CD rats were treated subcutaneously with 0, 0.1, 0.33,or 1.0 mg reserpine/kg/day either on Days 12–15 or onDays 16–19 of gestation. Dams were allowed to deliverand litters (4 ± 1 of each sex) were weighed weekly andheld to 21 days of age. Basal ornithine decarboxylase (ODC)activity and neurocheraical determinations were made on heartsand brains, respectively, from pups culled from litters on postnatalDay 1, and from two males and two females/litter at 21 daysof age. Following both treatment schedules, the high dose ofreserpine resulted in maternal weight loss during dosing, increasedstillborn pups, reduced pup weight at birth, retarded postnatalgrowth, and decreased survival to 21 days of age. Basal cardiacODC activity was reduced to 33% of control levels only on PostnatalDay 1 in both high-dose groups, while absolute heart weightdecreased and relative heart weight increased in these pups.Whole-brain concentrations of two neurotransmitter metabolites,3–4-dihydroxy-phenylacctic acid (DOPAC) and 5-hydroxyindoleaceticacid (5-HIAA), were increased only at Postnatal Day 1 in thehigh dose group treated on Days 12–15 of gestation. Noother changes were found in concentrations of these metabolitesor in the transmitters dopamine and serotonin. The only effectfound following administration of 0.33 mg/kg reserpine was areduction in maternal weight gained during both dosing periods.No signs of toxicity were observed following low-dose exposureon either schedule. Most previously reported postnatal functionalstudies following reserpine exposure have used mid- to late-gestationaltreatment with 1.0 mg/kg, a dose shown here to result in markedovert maternal and fetal toxicity. Such overt toxicity raisesthe question of whetheT the functional effects of reserpineare primary or may be secondary to general toxic effects. Suchquestions must be considered when interpreting postnatal functionaldata and in the design of further studies.     

Results of the NCTR Collaborative Behavioral Teratology Study (CBTS)*

Abstract Behavioral measures used in the CBTS were negative geotaxis, olfactory discrimination, auditory startle habituation, 1-hr and 23-hr activity, an operant discrete trial discrimination task, and activity following amphetamine challenge. Body weights and certain physical landmarks of development also were monitored in two separate studies, one using prenatal treatment with 0, 0.5 or 2.0 mg/kg d-amphetamine sulfate sc on gestation days 12-15, the other using 0, 2.0 or 6.0 mg/kg methylmercuric chloride by gavage on gestational days 6-9. An untreated control group also was included in each study. The CBTS design allowed evaluation of reproducibility and detection sensitivity of these methods, as well as the impact of early testing experience on later assessments, offspring sex differences in response levels and variability, and the contribution of litter-to-litter variation to behavioral measures used in this standardized protocol. Results obtained at the six participating laboratories are discussed in relation to each of these factors and to the degree of overt toxicity obtained with each compound. Behavioral data were reproducible, and detection sensitivities of the tests were very good, requiring no more than 5-25% change from control values for either sex. Early testing experience was not found to be a major factor in determining later behavioral levels, but litter was found to contribute considerable variability to all physical and behavioral data.