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Published on: November 20, 2015
Permanent motor activity and learning disorders induced by exposure to phenytoin during gestation and early infancy
Marcelo Javier Wolansky1, Julio Marcos Azcurra
1Interdisciplinary Project on Neuroteratology, Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Universidad de Buenos Aires, Buenos Aires, Argentina. wolansky.marcelo@epa.gov
Insights
Early exposure to phenytoin (PHT) in rats may worsen motor and learning deficits. Postnatal PHT exposure exacerbated long-term behavioral effects from prenatal PHT exposure, indicating increased vulnerability.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Behavioral Pharmacology
Background:
- Phenytoin (PHT) exposure during pregnancy is linked to motor and learning disorders in children.
- Limited data exists on long-term behavioral toxicity from infant PHT exposure.
Purpose of the Study:
- To investigate the persistence of PHT-induced behavioral alterations after gestational, infantile, or combined exposures.
- To assess the long-term impact of early life PHT exposure on motor and learning behaviors in rats.
Main Methods:
- Pregnant Sprague-Dawley rats received PHT or saline during gestation (GD 10-18).
- Offspring received PHT or saline during early postnatal development (PD 13-23).
- Circling behavior tests were conducted at PD40, PD80, and PD150 to assess motor control and learning.
Main Results:
- PHT exposure at any early stage increased circling velocity and spatial errors.
- Gestational PHT exposure led to persistent circling velocity increases at PD80 and PD150.
- Postnatal PHT exposure exacerbated the effects of gestational exposure on circling behavior.
Conclusions:
- Early life PHT exposure can induce lasting behavioral changes.
- Postnatal PHT exposure may worsen the long-term behavioral toxicity associated with prenatal PHT exposure.
- These findings highlight the vulnerability of developing nervous systems to PHT.
Abstract:
Experimental models and clinical data indicate that the incidence of motor and learning disorders may be increased in children of epileptic mothers taking phenytoin (PHT) during pregnancy. There is little data on the vulnerability of infants to PHT-induced long-term behavioral toxicity after gestational or early life exposure (i.e., infantile convulsion therapy). We examined the persistence of alterations in circling behavior induced by exposure to PHT during gestation, infancy, or both. Pregnant Sprague-Dawley rats were injected i.p. with saline (SAL) or PHT (30 mg/kg/day) during gestational days (GD) 10-18. The offspring were then administered (i.p.) SAL or PHT (60 mg/kg/day) during postnatal days (PD) 13-23. Afterward, Circling Training tests were performed at three time points. At PD40 and PD80, the clockwise direction of circling was reinforced. At PD150, counterclockwise circling was rewarded instead. At PD40, all PHT-treated groups demonstrated increased circling velocities compared to saline-treated controls. Higher spatial error rates for direction of circling were also observed in gestation-only and infancy-only exposures. At PD80, groups exposed during gestation had higher circling velocities than control or infancy-only exposed groups. At PD150, increases in circling velocity were apparent for the reverse learning task in groups exposed during gestation. These results indicate that early postnatal exposure to PHT may exacerbate the known long-term behavioral effects of gestational exposure.
