Differential effects of prenatal exposure to phenobarbital on the behaviour and neurochemistry of CBA and C57BL/6J mice

Abstract

Pregnant C57BL/6J and CBA mice were administered 60 mg/kg phenobarbital intraperitoneally from days 10 to 16 of gestation. On day 18 of pregnancy half of the control and drug-treated mice were killed and the embryonic brains removed for cell cultures. The remaining mice were allowed to have their litter. After cross-fostering the mice were used for behavioural studies. Pups born to drug-treated CBA mice had birth-weights similar to controls, but their weights had fallen behind controls by day 18 after birth. They were slower at attaining mature responses in tests for sensory motor development and became progressively more hyperactive (three times more active at day 18) compared to controls. Drug-exposed C57 pups also had birth weights similar to controls. After cross-fostering, 19% of control and 31% of drug-exposed pups died, but the remaining drug-exposed pups showed no deficits in weight gain. In contrast to drug-treated CBA pups, drug-exposed C57 pups were slightly quicker in attaining mature responses in some tests. There was no difference in activity between them and their controls. In neurochemical analyses, uptake of neurotransmitters by cerebral cultures from CBA showed that uptake of GABA was increased by 5%, choline by 95%, dopamine 120%, serotonin 165% and noradrenaline by 160% in cultures from drug exposed embryos compared to controls. In cerebral cultures from C57, GABA uptake was reduced by 18%, choline 33%, dopamine 35% and noradrenaline by 25%. Only serotonin uptake was increased by 182% compared to controls. Differences between C57 and CBA were also apparent in the uptake of neurotransmitters by neuronal cultures from the mesencephalon.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research

“…Consistent with reports of decreased weight of offspring, prenatal phenobarbital has been associated with a decrease in muscle mass at 12 weeks of age (adulthood begins at 8 weeks in rodents) [168]. The studies of Sedowofia [167] and Ihemelandu [168] are hard to compare because different doses and times of treatment during gestation were used. Nonetheless, effects on somatic development were found, suggesting it is a common effect that may occur regardless of dose and duration of in utero exposure.…”

“…However, in more recent studies in two different strains of mice (C3H and C57BL/6J), exposure to phenobarbital (∼0.5 mg/day) throughout gestation, a dose that is considered close to what would be a therapeutic dose in patients, had no effect on litter size or weight of the offspring [166]. In a separate study, exposure of mice (C57BL/6 and CBA) to phenobarbital in utero did not lead to a detectable effect on weight at birth, but weight of exposed mice was reduced at postnatal day (P)18 compared with controls [167]. Consistent with reports of decreased weight of offspring, prenatal phenobarbital has been associated with a decrease in muscle mass at 12 weeks of age (adulthood begins at 8 weeks in rodents) [168].…”

Economical Test Methods for Developmental Neurobehavioral Toxicity

“…natal sensory-motor development in mice of the DBA strain, whereas drug-exposed mice of the C57BL/6J strain were unaf? fected or slightly quicker in attaining mature responses in some tests (52). The considerable strain difference in response to treatment was also confirmed by the fact that only the DBA mice developed hyper?…”

Economical test methods for developmental neurobehavioral toxicity.

“…In one study, phenobarbital treatment on days 10 to 16 of gestation delayed postnatal sensory-motor development in mice of the DBA strain, whereas drug-exposed mice of the C57BL/6J strain were unaffected or slightly quicker in attaining mature responses in some tests (52). The considerable strain difference in response to treatment was also confirmed by the fact that only the DBA mice developed hyperactivity (up to three times the control level at 18 days); in addition, the profile of changes in uptake of neurotransmitters by cerebral cultures established with tissue removed shortly after the end of prenatal treatment differed markedly between the two strains.…”