Phencyclidine (PCP) is a widely abused drug (e.g. angel dust) which has a variety of actions in the central nervous system. Many of the behavioral effects induced by PCP are thought to result from the blockade of excitatory neurotransmission through the NMDA receptor. The activity of this receptor is critical for many normal brain functions including learning and memory. However, not all compounds that block the NMDA receptor have the same behavioral effects as PCP. Dextromethorphan is another non-competitive NMDA receptor antagonist that is thought to bind to the same site as PCP, but this drug has very different behavioral effects. The two major goals of this project are to understand the molecular interactions between the NMDA receptor and non-competitive antagonists like PCP and to determine the subunit composition and stoichiometry of the NMDA receptor. Several specific questions will be addressed during the course of the project including: l) are there subtypes of NMDA receptors which interact differently with PCP, 2) How are subtypes of NMDA receptors assembled from various subunits, 3) what is the stoichiometry of the NMDA receptor, 4) Which regions of the NMDA receptor bind PCP 5) Which amino acids in the NMDA receptor are most important for drug binding, 6) do amino acids from multiple NMDA receptor subunits interact with PCP, 7) do all non-competitive agonists of the NMDA receptor bind to the same subtypes of NMDA receptor, 8) is it feasible to develop drugs to block PCP binding which will not block the NMDA receptor channel.
