Related Experiment Videos
Learning/memory impairments in rat offspring prenatally exposed to phenytoin
1Laboratory for Drug Safety, Nippon Hoechst Marion Roussel Limited, Saitama-ken, Japan.
Insights
Phenytoin exposure in pregnant rats impaired offspring learning and memory, particularly working memory. The radial maze effectively detected these cognitive deficits, linked to altered neuropeptides and fetal brain injury.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Cognitive Science
Background:
- Phenytoin (PHT) is an anticonvulsant medication with known teratogenic potential.
- Prenatal exposure to certain drugs can lead to long-term neurodevelopmental deficits in offspring.
Purpose of the Study:
- To investigate the effects of prenatal phenytoin exposure on cognitive function and neurodevelopment in rat offspring.
- To identify sensitive behavioral tasks for detecting learning and memory impairments induced by phenytoin.
Main Methods:
- Pregnant rats were administered phenytoin (50 and 100 mg/kg/day) during gestation (days 7-18).
- Offspring were assessed using a battery of behavioral tests including negative geotaxis, figure-eight maze, Biel water maze, Morris maze, radial maze, and delayed nonmatching-to-sample test.
- Brain weights and neuropeptide levels in specific brain regions were measured.
Main Results:
- Prenatal phenytoin exposure delayed the maturation of negative geotaxis.
- The radial maze and delayed nonmatching-to-sample test revealed significant learning and working memory impairments in offspring.
- Altered neuropeptide concentrations were observed in the mesolimbic cortex, hippocampus, and amygdala.
- Reduced brain weights were noted at 6 weeks but normalized by 16 weeks in the higher phenytoin dose group.
Conclusions:
- The radial maze is a sensitive tool for detecting learning and memory deficits caused by prenatal phenytoin exposure.
- Working memory impairment, potentially due to abnormal neuropeptide changes and fetal hippocampal injury, underlies the observed learning deficits.
Abstract:
Phenytoin (PHT) was orally administered in dosages of 50 and 100 mg/kg/day to pregnant rats on days 7-18 of gestation. Offspring were tested on the negative geotaxis test, a figure-eight maze (F8), the Biel water maze (BM), the Morris maze (MM), and the radial maze (RM). In addition, a delayed nonmatching-to-sample (DNMTS) test was employed. The levels of neuropeptides in brain and brain weights were determined. The maturation of negative geotaxis was delayed in both PHT groups. PHT groups showed no differences in F8, BM, and MM. In the RM, the total number of choices was high, whereas the number of correct choices was low. In the DNMTS, PHT groups showed low for correct choices with a long interval. The concentrations of neuropeptides were changed in the mesolimbic cortex, hippocampus, and amygdala. Brain weights were lower at 6 weeks of age in the 100 mg/kg/day PHT group, but were comparable at 16 weeks of age. This study suggests that the RM is a detectable task for the learning/memory impairments induced by PHT. In addition, it is surmised that the learning deficit is due to a working memory impairment arising from abnormal changes in neuropeptides and an injury in the fetal hippocampus.