Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats

Pregnant Sprague-Dawley rats were treated with 0, 150 or 200 mg/kg valproic acid by gavage (VPA) on days 7–18 of gestation. These doses produced no maternal toxicity, reproductive effects or effects on offspring growth and survival. Maternal plasma VPA peak levels averaged 99 and 134 μg/ml 1 h after the last treatment, values approximating human therapeutic levels. VPA offspring tested after weaning exhibited reduced open-field central, but not peripheral, activity and reduced hole-board horizontal, but not vertical, activity. No activity differences were found in a figure-8 test or on a preweaning activity test. The VPA offspring also showed lengthened straight channel swimming times, increased swimming maze errors, but only among the females, while producing no differences in maze times. VPA offspring exhibited reduced spontaneous alternation frequency and reduced startle responding to both auditory and tactile (air-puff) stimuli. The effects of VPA were dose dependent in some cases (straight channel swimming and water maze errors), or the effect was seen only in the high-dose group (open-field, hole-board, spontaneous alternation, startle). The conclusion was reached that prenatal VPA is behaviorally teratogenic in rats at relevant maternal blood concentrations and at non-malforming doses.

[1]  David W. Smith,et al.  Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. , 1976, The Journal of pediatrics.

[2]  Fetal hydantoin syndrome. , 1975, Lancet.

[3]  Michael Davis.  The Mammalian Startle Response , 1984 .

[4]  C. Vorhees.  Fetal anticonvulsant syndrome in rats: effects on postnatal behavior and brain amino acid content. , 1984, Neurobehavioral toxicology and teratology.

[5]  E. Zackai,et al.  The fetal trimethadione syndrome. , 1975, The Journal of pediatrics.

[6]  L. Middaugh,et al.  Phenobarbital during pregnancy alters operant behavior of offspring in C57BL/6J mice , 1975, Pharmacology Biochemistry and Behavior.

[7]  A. Czeizel,et al.  VALPROIC ACID AND SPINA BIFIDA , 1982, The Lancet.

[8]  S. Fabro,et al.  Teratogenicity of valproic acid: In vivo and in vitro investigations , 1981 .

[9]  H. Nau,et al.  A new model for embryotoxicity testing: teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations. , 1981, Life sciences.

[10]  C. Curry,et al.  The fetal valproate syndrome. , 1984, American journal of medical genetics.

[11]  C. Vorhees.  Maze learning in rats: a comparison of performance in two water mazes in progeny prenatally exposed to different doses of phenytoin. , 1987, Neurotoxicology and teratology.

[12]  B. Dalens,et al.  Teratogenicity of valproic acid. , 1980, The Journal of pediatrics.

[13]  C. Vorhees,et al.  Teratogenicity and developmental toxicity of valproic acid in rats. , 1987, Teratology.

[14]  T. G. Hayes,et al.  Teratogenic effects of dosage levels and time of administration of carbamazepine, sodium valproate, and diphenylhydantoin on craniofacial development in the CD-1 mouse fetus. , 1984, Journal of craniofacial genetics and developmental biology.

[15]  M. R. Gomez.  Possible teratogenicity of valproic acid. , 1981, The Journal of pediatrics.

[16]  C. Vorhees.  Fetal anticonvulsant syndrome in rats: dose- and period-response relationships of prenatal diphenylhydantoin, trimethadione and phenobarbital exposure on the structural and functional development of the offspring. , 1983, The Journal of pharmacology and experimental therapeutics.

[17]  F. Sullivan,et al.  Effect of prenatal phenytoin administration on postnatal development of the rat: a behavioral teratology study. , 1981, Teratology.

[18]  M. Bantz.  Valproic Acid and Congenital Malformations , 1984, Clinical pediatrics.

[19]  D. Lindhout,et al.  SPINA BIFIDA AND IN-UTERO EXPOSURE TO VALPROATE , 1984, The Lancet.

[20]  M. Tassinari,et al.  Behavioral outcome after prenatal exposure to phenytoin in rats. , 1983, Teratology.

[21]  J. Petrere,et al.  Teratogenesis of calcium valproate in rats. , 1983, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[22]  M. Cutler,et al.  Sodium valproate: Effects on social behaviour and physical development in the mouse , 2004, Psychopharmacology.

[23]  E. Robert,et al.  MATERNAL VALPROIC ACID AND CONGENITAL NEURAL TUBE DEFECTS , 1982, The Lancet.

[24]  R. Douglas.  Cues for spontaneous alternation. , 1966, Journal of comparative and physiological psychology.

[25]  R. McGivern,et al.  Prenatal alcohol exposure alters adult expression of sexually dimorphic behavior in the rat. , 1984, Science.