| Rats exposed to phenytoin (PHT) in utero demonstrate abnormal circling, decreased learning, hyperactivity, and delayed air righting reflex. These behavioral deficits were hypothesized to be due to neuronal cell death in the regions involved in these behaviors (vestibular, motor control, and cortical regions). This neuronal damage was further hypothesized to be identified by neurochemistry (neuronal markers) and/or functional assays (modifications of the Morris Water Maze (MWM)). Five experiments were performed to address these hypotheses.; Phenytoin-exposed offspring had replicable increases in preweaning mortality, growth retardation, abnormal circling, and impaired learning (as demonstrated in the Cincinnati Maze and MWM). Identification of brain regions demonstrating PHT neurotoxicity was not possible using a variety of neuronal markers (Glial Fibrillary Acidic Protein, Microtubule Associated Protein-2, Neuron Specific Tubulin, Hemotoxylin & Eosin) and time points (embryonic day 14, postnatal days 3, 7, 14, 21, and 28) employed during these studies.; Modifications of the MWM indicate that the PHT-Non-Circling (PHT-NC) offspring demonstrate impaired spatial learning (during acquisition and reversal), but not spatial memory, short-term memory or discrimination. The PHT-Circling (PHT-C) group demonstrates impaired spatial reference learning/memory, visible platform, visible, and spatial discrimination, and spatial working memory performance. Deficits during proximal cue tasks make interpretations about the spatial reference and discrimination tasks difficult. Offspring exposed prenatally to PHT demonstrate either (1) impaired spatial reference learning, or (2) abnormal circling; impaired spatial working memory; sensorimotor, motivational, or generalized learning deficits; and possibly impaired spatial reference and/or discrimination learning. |
