Chronic prenatal exposure to carbamazepine and behavior effects on mice offspring.

OBJECTIVE: The purpose of this study was to assess the impact of chronic prenatal exposure to a therapeutic dose of carbamazepine on the behavior of mice offspring in a randomized, placebo-controlled manner. STUDY DESIGN: Twenty-eight C3H/He mice were assigned randomly to treatment groups that were given food that contained either carbamazepine (25 mg in 10 g food) or a placebo for 1 week before mating and throughout gestation. Adult offspring from eight litters of each group were evaluated for standard tasks for motor, arousal/motivation, anxiety, and cognition. Statistical comparisons included analysis of variance and the Fisher exact test. RESULTS: Compared with the placebo group, there were no significant differences among the carbamazepine offspring in the duration of gestation, litter size, and birth weights. Fewer locomotor chamber movements were recorded in the carbamazepine group than in the placebo-exposed group at postnatal day 21 (469 vs 555 counts for 60 minutes, P<.03) and as adults (510 vs 688 counts for 60 minutes, P<.03) Coordination, balance, and exploratory behavior did not differ between exposure groups. A startle response from auditory arousal was decreased in carbamazepine-exposed adults (1.4% vs 21.9%, P<.03). Performances on anxiety/motivation tasks and on learning/memory tasks revealed no significant differences between exposure groups. CONCLUSION: Although prenatal exposure induced subtle arousal effects and slower locomotor activity, carbamazepine did not have an impact on coordination, cognition, or responses to anxiety-provoking conditions. Correlation in humans is recommended.

Chronic prenatal exposure to carbamazepine and perinatal outcomes of C3H/He mice.

OBJECTIVES: This study was undertaken to determine a daily therapeutic dose of carbamazepine and to measure its effect on reproductive performance and perinatal outcomes of mice. STUDY DESIGN: Adult C3H/He mice were given carbamazepine in rodent chow in either a 0.25% or a 1.0% mixture. Comparisons between doses included nongravid weight change, plasma drug steady-state concentrations, and response to a maximal electroshock seizure test. The strain was then fed either the preferred dose of carbamazepine or a placebo 1 week before starting to mate and throughout gestation to compare reproductive performance and offspring early development. RESULTS: Mice who ate the 0.25% carbamazepine mixture displayed no evoked seizure activity and, in contrast to the 1.0% mixture, did not lose weight. This daily dose of 542+/-35 mg/kg produced a trough steady-state plasma concentration that was consistent with a protective threshold in humans. Differences from placebo controls were not statistically significant for the number of cycles necessary to conceive or for the duration of gestation. The litter size, survival rates, birth weights, weight gain, and onset of eye openings and teeth eruptions of the pups were not statistically significant between the two groups. CONCLUSION: Long-term prenatal exposure to a subtoxic yet therapeutic dose of carbamazepine did not impair reproductive performance or early growth and development of exposed mice offspring.

Effects from prenatal exposure to alprazolam on the social behavior of mice offspring.

OBJECTIVE: The purpose of this study was to conduct, in a randomized placebo-controlled manner, social behavior testing on mice offspring that were exposed prenatally to alprazolam. STUDY DESIGN: A previously described, clinically relevant dose of 0.32 mg/kg of alprazolam (n=8 mice) or a placebo (n=9 mice) was given to gravid C57BL/6 mice by gavage on gestational day 18. Social play, sleep/wake patterns, and male aggression of the exposed offspring were assessed during prejuvenile, juvenile, and adult periods. RESULTS: Alprazolam did not produce treatment differences in pregnancy outcomes or in dam-pup interactions. Compared with the placebo group, alprazolam-exposed offspring demonstrated less desire to escape (P<.01), more desire to remain alone (P<.02), and shorter periods of being awake (P<.03) on PND 17. Alprazolam-exposed male offspring exhibited more aggression on food restriction (P<.01) and on cage changing (P<.01). CONCLUSION: Mice offspring that were exposed prenatally to alprazolam demonstrated more individual rather than group activities, avoidance of open areas, and aggression in males. Correlation of these findings in humans is encouraged.

Systemic administration of betamethasone delays endotoxin-induced preterm labor in the murine model.

OBJECTIVE: The purpose of this study was to determine whether the administration of betamethasone decreases the endotoxin-induced preterm parturition rate and inhibits the risk of cytokines in the murine model. STUDY DESIGN: Endotoxin was administered intraperitoneally at gestational day 15 (75% of gestation). In phase I, the duration of gestation was measured in 36 gravid C3H/HeOu mice that were equally divided into four treatment groups: control, endotoxin only, and two different dose regimens of betamethasone followed by endotoxin. In phase II, maternal serum and amniotic fluid concentrations of cytokines (interleukin-1alpha, tumor necrosis factor-alpha, and interleukin-6) were measured at 4 hours after endotoxin injection in 44 gravid mice divided equally in the four treatment groups. RESULTS: The group that was exposed only to endotoxin was delivered at a significantly earlier gestational age compared with the control group (16.2 +/- 0.4 days vs 19.6 +/- 0.2 days; P <.01). The two groups that were pretreated with betamethasone before the endotoxin were delivered at gestational ages similar to the control group. There was a marked increase of tumor necrosis factor-alpha and interleukin-6 levels in amniotic fluid of mice that were treated with endotoxin only compared with the control group (P <.001). No difference in cytokine levels was found in those mice that were premedicated with betamethasone compared with the control group. CONCLUSION: Antenatal administration of betamethasone to mice delayed preterm parturition that was induced by endotoxin. Elevations of amniotic fluid cytokine concentrations that were observed with endotoxin were not observed with pretreatment with betamethasone.

Neurobehavior effects in four strains of mice offspring exposed prenatally to alprazolam.

OBJECTIVE: This study was performed to determine whether prenatal exposure to alprazolam affects offspring behavior in different strains of mice. STUDY DESIGN: Eight to 11 gravid mice of the C3H/He, C57BL/6, A/J, and DBA/2 strains were given either an anxiolytic dose of alprazolam (0.32 mg/kg) or a placebo by gavage on day 18 of an anticipated 19- to 21-day gestation. Neurobehavior tasks were conducted to assess anxiety, learning and memory, and social interaction. Data were analyzed by analysis of variance or a Fisher exact probability test. RESULTS: Anxiety in alprazolam-exposed offspring was reduced in C3H/He (P <.05) and A/J (P <.05) newborn infants by separation vocalization but may be increased in the C3H/He adult strain on the plus maze task. Learning was slower among C57BL/6 mice exposed to alprazolam (P <.01), whereas memory was reduced in exposed A/J and DBA/2 offspring (P <.05). Alprazolam exposure was associated with more aggression among C3H/He and C57BL/6 male offspring (P <.01) and with less group activity by C57BL/6 offspring (P <.05). CONCLUSION: Altered behaviors in several mouse strains after prenatal exposure to alprazolam suggests a vulnerability of GABA-benozdiazepine receptor formation in fetal brain development.