Fetal anticonvulsant syndrome in rats: effects on postnatal behavior and brain amino acid content

A series of experiments were conducted using Sprague-Dawley CD rats to develop an animal model of the behavioral effects associated with the fetal anticonvulsant syndromes. The anticonvulsants investigated were diphenylhydantoin (DPH), trimethadione (TMD), and phenobarbital (PB). In Exp.-1 the lower end of the teratogenic dose-response curve was determined for each drug. From this information a dose was chosen that was sub-teratogenic for DPH (200 mg/kg) and TMD (250 mg/kg), and marginally teratogenic for PB (80 mg/kg). In Exp.-2 these doses and two lower doses of each drug were administered on days 7-18 of gestation and the offspring evaluated for behavioral teratogenicity. The major effects were that the DPH200 offspring showed increased pivoting, delayed auditory startle development, delayed swimming ontogeny, increased mortality, reduced weight, increased figure-8 activity accompanied by reduced rearing, increased swimming maze errors and times, and impaired passive avoidance retention at the two-week retention test interval. The TMD250 group also showed delayed swimming ontogeny, increased figure-8 activity and maze times, and decreased spontaneous alternation behavior. The PB80 group showed delayed swimming ontogeny as its major behavioral effect. In Exp.-3 the same dose at which effects were found in Exp.-2 were given during one of three periods during gestation (days 7-10, 11-14, or 15-18) to determine period-response effects. Similar behavioral effects were found as in Exp.-2 and for DPH which were primarily associated with 11-14 day exposure and to a lesser extent with exposure on days 7-10 and 15-18. The effects of TMD were also similar to those seen in Exp.-2 and were most pronounced during days 7-10 and 15-18 with lesser effects on days 11-14. The effects of PB were again limited to delayed swimming ontogeny and were primarily during the 7-10 and 11-14 day exposure periods. In Exp.-4 the maternal plasma levels of DPH were determined at 1, 4 and 6 hours after the last treatment on day 18 of gestation with 100, 150, or 200 mg/kg. At all time points the 100 mg/kg dose produced plasma DPH levels averaging around 10 micrograms/ml, the 150 mg/kg dose levels averaging 20 micrograms/ml, and the 200 mg/kg dose level averaging 24 micrograms/ml. The highest values exceed the human therapeutic range, but the levels at 100 and 150 mg/kg are within the therapeutic range.(ABSTRACT TRUNCATED AT 400 WORDS)