Hippocampal degeneration inducing impairment of learning in rats: Model of dementia?

In the pharmacological held, the development of drugs effective for dementia is now widely anticipated because of the increase in the elderly population. Dementia has some histological degeneration in the brain, including the hippocampus. Preclinical evaluations of such drugs use animal models with memory impairment, since memory impairment is a major criterion of dementia. We therefore investigated two animal models with hippocampal degeneration. Neonatal administration of monosodium glutamate (MSG) induced specific degeneration of hippocampal pyramidal cells in the CA1 region of Wistar rats in adulthood. In these animals, the correct response rate during the acquisition period of light-dark discrimination learning was significantly lower than that in the control group. No significant changes were noted in the hippocampal concentrations of neurotransmitter substances, including acetylcholine and glutamate. In the second model, similar histological changes were observed at 3 weeks after oral administration of trimethyltin (TMT). These histological changes were accompanied by a reduction in the intrahippocampal concentrations of acetylcholine and glutamate. In the case of light-dark discrimination learning, neither pre- nor post-training administration of TMT affected the correct response rate during both the acquisition and retention test periods. In the case of 8-arm radial maze learning, the increase in correct response rate was significantly suppressed in comparison with that of the control group when TMT was administered at 4 weeks before starting the acquisition trial. This suppression was followed by a lower response rate in the retention test. On the other hand, the correct response rates in retention tests were not affected when TMT was administered after completion of the acquisition trial. These findings indicate that sole degeneration of the hippocampus was able to induce different types of memory impairment, and single evaluation of a drug with one learning paradigm was difficult to justify that a drug is effective for dementia.