It has been shown repeatedly that antagonists of the NMDA subtype of glutamate receptor interfere with performance on learning/memory tasks and also block the induction of hippocampal long term potentiation (LTP). It is generally believed, but without directly supporting evidence, that the ability of NMDA antagonists to block hippocampal LTP induction underlies the apparent memory impairing actions of these compounds. However, in view of the applicants' finding that NMDA antagonists, at subcutaneous doses which do not have damaging effects on hippocampal neurons, cause acute pathomorphological changes in posterior cingulate neurons, the question arises whether the impaired learning/memory performance associated with these compounds might relate more to their brain damaging action in the cingulate cortex than to postulated interference in hippocampal LTP. The applicants have shown that anticholinergic drugs prevent the cingulate neurotoxic side effects of NMDA antagonists, and they have developed preliminary evidence that anticholinergic drugs may also counteract the impaired acquisition performance induced by NMDA antagonists. In the present Project, these preliminary findings will be further explored and, as in our previous work, we will systematically investigate the role that nonassociative factors such as sensorimotor disturbances may play in affecting performance on our learning/memory measures. In another series of experiments, we will administer high doses of the NMDA receptor antagonist MK-801 to rats in order to create extensive bilateral necrosis in the posterior cingulate/retrosplenial cortices, and the rats will be tested behavioraIly to determine if this treatment impairs learning/memory or other behavioral functions. In this Project we will also conduct electrophysiologic studies that are parallel to our behavioral work in that they will focus on whether anticholinergic drugs prevent NMDA antagonists from blocking the induction of hippocmpal LTP. In addition, we will attempt to induce LTP in the in vivo cingulate cortex and, if successful, we will determine whether MK-801 blocks cingulate LTP and whether anticholinergic agents prevent MK-801 from blocking cingulate LTP. It is expected that these experiments may help clarify the locus of action and mechanism by which NMDA antagonists may impair learning/memory performance while also clarifying what role, if any, either hippocampal or cingulate LTP plays in the apparent memory disrupting process.
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