Diazepam‐induced cleft palate in the Mouse: The role of endogenous maternal corticosterone

Abstract

The 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.

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

“…However, later studies were unable to confirm these observations . Structural abnormalities were also found in rodents following in utero BZD exposure, with an enhanced frequency in cleft palate (Miller and Becker, 1975;Barlow et al, 1980), exencephaly, and limb malformations, as well as rib defects at higher doses (Buttar, 1980). Differences in sample size, exposure length, type of BZD administered, and the animal species used might explain the lack of consistency in the findings regarding the potential teratogenic effects of in utero BZD exposure reported in the literature.…”

Acute Studies to Investigate the Mechanism of Action of Caffeine as a Teratogen in Mice

“…In fact the corticosterone levels produced by caffeine in the present experiment are very similar to those previously observed by us in the same strain of mouse, Charles River CD 1, following injection of 2.5 mg corticosterone. In these previous experiments following injection of 2.5 mg corticosterone, the plasma corticosterone levels at 1 and 6 h were 1053 ± 137, and 643 ± 143 ~g per 100 ml, and also caused cleft palates with an incidence of 8-25% of fetuses (in 43-71 % of litters) (Barlow et al, 1980). An important factor in induction of cleft palate in mice, however, is not just the peak height of the corticosterone response but also the duration of the response above some critical level for a period of at least 6 h (Barlow et al, 1975;.…”

“…It is interesting that the most sensitive day for the induction of cleft palate was day 14 since we have previously found this to be the most sensitive day for induction of cleft palate following stress or corticosterone injections in I.C.I. mice (Barlow, McElhatton & Sullivan, 1975) and following stress, corticosterone or diazepam in CD1 mice (Barlow, Knight & Sullivan, 1980). Having established day 14 as the sensitive day for caffeine-induced cleft palate, all of the acute studies to investigate its mode of action as a teratogen were carried out on day 14 pregnant mice.…”

Species sensitivities and prediction of teratogenic potential.

“…Therefore, the mouse would seem unsuitable for the testing of such agents as sedatives, tranquilizers, hypnotics or agents requiring unusual, manipulative procedures. The rat and rabbit are less prone to stressinduced teratogenicity (20,21). A lack of steroid-induced cleft palates in man led Tuchmann-Duplessis (6) to conclude that the unique susceptibilities encountered with various mouse strains may lead to many false positives.…”