NMDA ANTAGONISTS AS NEUROTHERAPEUTIC DRUGS, PSYCHOTOGENS, NEUROTOXINS, AND RESEARCH TOOLS FOR STUDYING SCHIZOPHRENIA

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate (G lu) receptor have become the focus of considerable attention as potent ial neurotherapeutic agents in view of mounting evidence implicating N MDA receptors in acute central nervous system (CNS) injury syndromes s uch as stroke, trauma, and status epilepticus. In addition, NMDA recep tor antagonists are of potential interest for the clinical management of neuropathic pain and preventing the development of tolerance to opi ate analgesics. A potentially serious obstacle to the development of N MDA antagonists as neurotherapeutic drugs is the paradoxical fact that whereas these agents do have significant neurotherapeutic potential, they also have psychotogenic and neurotoxic properties. We have been i ntensively investigating the mechanisms underlying these adverse prope rties and have discovered several methods of suppressing or preventing their expression. In addition, we have been exploring the possibility that a common mechanism may underlie the psychotogenic and neurotoxic actions of these agents and that this mechanism may have relevance to the pathogenesis of idiopathic psychotic processes such as schizophre nia. In this chapter, we will review our findings pertaining to NMDA a ntagonists in the dual context of their value as tools for exploring m echanisms underlying neuropsychiatric disturbances, particularly schiz ophrenia, and their potential promise as therapeutic agents. For addit ional references and a more complete elaboration of our hypothesis per taining to NMDA receptor dysfunction and schizophrenia, please see a r ecent review (Olney and Farber 1995).