ABSTRACT
A positive control study was conducted as part of the ongoing validation program for developmental neurotoxicity testing in our laboratory using a standard battery of automated systems, consisting of rotorod, motor activity, acoustic startle, and two-way active avoidance. Female Sprague-Dawley rats were given 10 mg/kg diazepam (DZ) by SC injection or 20 mg/kg methimazole (MET) by gavage from gestation day 15 (DZ) or 17 (MET) through postpartum day 10; a group of control animals remained untreated. Offspring were assessed for growth, survival, developmental landmarks, and behavior. Although this study was considered useful for obtaining historical data, it offered few advantages in terms of validation of automated behavior test systems. Perinatal treatment with DZ resulted in no maternal toxicity and no adverse effects on growth or development of F1 offspring; a deficit in acoustic startle responding was the only behavioral effect observed. Treatment with MET resulted in maternal toxicity, reduced neonatal body weights, and developmental delays. Behavioral effects included impaired rotorod performance and acoustic startle responding (neonates), and enhanced motor activity and acoustic startle responding (young adults). However, effects on shuttle avoidance were not observed for either drug, and only one direction of behavioral effect occurred for the rotorod and motor activity systems. These results, as well as those from subsequent studies in our laboratory, suggest that it may be preferable to validate automated behavior systems using short-term studies in which young adult animals are treated directly with positive control agents.
