TBI. Animals will be trained on the passive avoidance task at various post-TBI times(1, 15, 39, 60 days) and either a cholinergic (scopolamine) or NMDA (MK-801) antagonist will be administered prior to the training trial. These results will identify the receptor systems that contribute to this TBI-induced cognitive dysfunction and will establish the time course of altered receptor function during the maintenance phase of the injury process. The second specific aim will examine whether chronic exposure to an intervention that enhances neuronal function will promote the recovery of several indexes of cognitive function after TBI. After 15 days of exposure to an enriched or a standard environment following TBI, animals will be tested for sensitivity to cholinergic and NMDA memory disruption, LTP, and Morris water maze (MWM) performance. In order to examine whether this intervention that improves cognitive performance will also normalize the chronic aberrant receptor-effector function that follows TBI, carbachol-stimulated IP production and cholinergic and NMDA receptor binding assays will be performed following exposure to an enriched environment. The third specific aim will investigate whether pharmacological manipulations that enhance the activity of specific receptor systems during the chronic (maintenance) phase will reduce the long-term cognitive impairment associated with TBI. Experiments will test the effectiveness of THA (a cognitive enhancing acetylcholinesterase inhibitor) and D-cycloserine (a cognitive enhancing NMDA/glycine partial agonist). Various doses of each drug will be administered during the maintenance phase of the injury process and their efficacy in reducing the long-term impairment of cognitive function will be examined.
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