The excitatory amino acids (EAA), glutamate (Glu) and aspartate, are major excitatory transmitters in the CNS and also have potent neurotoxic (excitotoxic activity which is mediated through EAA synaptic receptors. Several EAA receptor subtypes have been identified, the N-methyl aspartate (NMA) receptor being the best characterized and comprising the majority of EAA receptors in brain. It was recently found that drugs in the PCP/sigma opiate category powerfully and selectively block both the excitatory and toxic effects of NMA on central neurons. Also, it has been shown that NMA and PCP receptors have nearly an identical distribution pattern throughout rat forebrain. The ability of PCP to powerfully inhibit EAA transmission raises the important question whether this might be the mechanism underlying PCP psychotomimetic effects and, if so, whether impaired EAA transmitter function might underlie schizophrenia and/or other psychotic processes. Recent evidence also implicates NMA receptors in long term potentiation, a phenomenon putatively mediating memory formation, which suggests an EAA-linked mechanism by which PCP might interfere with memory. Currently there is considerable interest in the possibility that NMA antagonists might be useful neuroprotective agents in the clinical management of neurodegenerative conditions such as cerebral ischemia (at the potential risk of inducing psychotomimetic effects or memory impairment). We are requesting support for a series of in vitro studies that will generate information relevant to the above. In the chick embryo retina we will study the mechanism(s) by which PCP/sigma opiate compounds block NMA neurotoxicity and will compare PCP/sigma opiate compounds with other EAA antagonists for efficacy in preventing ischemic neuronal degeneration. In cultured chick spinal neurons we will apply voltage and patch clamp techniques to explore the mechanism(s) by which PCP/sigma opiate compounds antagonize the excitatory action of NMA. In rat hippocampal slices we will study the ability of PCP/sigma opiate compounds to block long term potentiation.
