Developmental, Neuro and Immunotoxic Effects of Perinatal Diazepam Treatment in Rats

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Abstract
In utero exposure of rats to low dosages of diazepam (1.0—2.0 mg/kg) has been found to result in depression of the cellular and humoral immune responses during adulthood. Behavioral dyshnctions were also reported in infants from mothers with high benzodiazepine (BDZ) intake during pregnancy. The present experiment was undertaken to reconsider the potential action of diazepam during ontogeny in order to obtain hrther information about developmental processes using a refined methodology. Time-pregnant rats were treated subcutaneously with diazepam (2.0 mg/kg/day: group E1) or with diazepam vehicle (group C) from gestational day 14 to 20. Other dams (group E2) received the same BDZ dose from the 1st to the 21st day of lactation (weaning) or were not treated, remaining undisturbed in their home cages (group C2). The following results were obtained for animals perinatally treated with diazepam compared to groups C1 and C2: 1- increased time for testis descent and decreased time for vaginal opening (group E2); 2- no changes in the dates for ear end eye opening, or incisor tooth eruption (groups E1 and E2); 3- increased locomotor activity in the open-field (group E2) and/or in the plus maze (groups E1 and E2); 4- decreased levels of anxiety measured in the plus maze (goups E1 and E2); 5- decreased macrophage spreading and phagocytosis (groups E1 and E2). These results, which occurred in the absence of overt signs of maternal or fetal toxicity, demonstrate developmental, neuro- and immunotoxic effects of perinatal diazepam treatment in rats.