Diazepam-induced cleft palate in the mouse: the role of endogenous maternal corticosterone.

Abstract

AbstractThe aims of the experiments were to investigate the effects of diazepam treatment on day 14 of pregnancy in the mouse on endogenous maternal plasma corticosterone levels and induction of cleft palate (CP) in the offspring, and to evaluate any interaction between diazepam and stress‐induced or corticosterone‐induced CP. Sub‐teratogenic doses of diazepam (10 mg/kg orally, given t ice 12h apart) had no significant effect on the induction of CP by 24h maternal food deprivation. Similarly, neither sub‐teratogenic doses (10 or 50 mg/kg, given twice) nor teratogenic doses (100 mg/kg, given twice) of diazepam had any significant effect on the induction of CP by exogenous corticosterone given at low (2.5 mg) or high (10 mg) doses. However, diazepam alone (10‐400 mg/kg) raised endogenous plasma corticosterone levels in a dose‐related way. Mice given teratogenic doses of diazepam, 100 or 200 mg/kg, causing 3‐6% CP, sustained elevated endogenous corticosterone levels for at least 6h after dosing, in comparison with sub‐teratogenic doses of diazepam or vehicle controls. In a comparison of mice given 400 mg/kg diazepam, causing 20% CP, with mice given 2.5 mg corticosterone, causing 25% CP, the mean endogenous corticosterone level was lower in the diazepam group at 1h but higher at 6h after dosing than that of the exogenous corticosterone group. These results suggest that diazepam may cause CP in the mouse by raising endogenous maternal corticosterone levels. The stress of fasting and immobilisation resulting from the heavy sedation caused by teratogenic doses of diazepam may contribute to the elevations in endogenous corticosterone levels.