The primary purpose of this proposal is three-fold: 1) to continue to evaluate the behavioral effects of drugs that act as agonists or antagonists at the NMDA subtype of the glutamate (excitatory neurotransmitter) receptor; 2) to begin to understand more of the behavioral pharmacology of nitric oxide primarily by using nitric oxide synthase inhibitors; and 3) to use newly available drugs that have parenteral activity to study the behavioral pharmacology of the AMPA subtype of the glutamate receptor. With respect to item 1), it has been found that the NMDA receptor contains sites for glycine as well as glutamate, and both of these excitatory amino acids ar necessary to activate this receptor. We have studied the interaction between agonists and antagonists at both these sites extensively in the mouse. The current proposal will extend these interaction studies to the pigeon and the monkey using primarily rates of food-maintained responding and discriminative stimulus effects as assays. With respect to item 2), it has been found that activation of the NMDA receptor results in production of nitric oxide from L-arginine, catalyzed by nitric oxide synthase. Similar effects of nitric oxide synthase inhibitors and PCP have been found in our studies of the discriminative stimulus effects of PCP. Part of the rationale for the proposed studies is to determine how much of the effects of PCP-like drugs and other NMDA antagonists and agonists are through NO formation. With respect to item 3), there has been very little work done on the in vivo effects of AMPA agonists and antagonists, because parenterally active drugs are only recently available. The behavioral effects of these drugs will be evaluated during this grant period. In addition to the effects of a number of EAA agonists and antagonists on rates of responding and their ability to serve as discriminative stimuli, a number of studies of the effects of these drugs on learning and memory in the pigeon are planned. Each of the three areas described above (glycine:glutamate; NO; AMPA) have well-characterized effects on long-term potentiation in the hippocampus, and less well-characterized effects on learning in animals. This is a fascinating and important area that will be explored in depth in this grant period.
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