Learning/memory impairments in rat offspring prenatally exposed to phenytoin.
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.
Tsutsumi
S
S
Laboratory for Drug Safety, Nippon Hoechst Marion Roussel Limited, Saitama-ken, Japan.
Akaike
M
M
Ohno
H
H
Kato
N
N
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects*; D005260:Female; D007858:Learning / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D009478:Neuropeptide Y / Q000032:analysis; D009929:Organ Size / Q000187:drug effects; D010672:Phenytoin / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000032:analysis
D009478:Neuropeptide Y; D013004:Somatostatin; D010672:Phenytoin