BEHAVIORAL-APPROACHES TO THE FUNCTIONAL ASSESSMENT OF NMDA-MEDIATED NEURAL TRANSMISSION IN INTACT MICE

Altered neurotransmission mediated by L-glutamate at the level of the N-methyl-D-aspartic acid (NMDA) receptor complex has been implicated i n the pathophysiologic mechanisms of several major neuropsychiatric di sorders. Moreover, strategies for the pharmacologic manipulation of NM DA-mediated neural transmission have been discussed for the treatment of disorders as diverse as schizophrenia, seizures, stroke, and trauma tic brain injury. MK-801, an uncompetitive allosteric antagonist of th e NMDA receptor complex, was shown to antagonize electrically precipit ated seizures in a dose-dependent manner and elicit popping behavior i n mice. Changes in the ability of MK-801 to antagonize electrically pr ecipitated seizures or elicit popping behavior caused by stress or pha rmacologic manipulations may reflect alterations in the populations of NMDA-associated channels responsible for these behavioral actions (e. g., the number of them in the open configuration or their size, shape, and charge characteristics). We used these paradigms to study the pha rmacologic actions of an allosteric glycinergic intervention (i.e., mi lacemide), inhibitors of the ''nitric oxide cascade'' (i.e., 7-nitroin dazole and methylene blue), and conventional (i.e., haloperidol) and a typical (i.e., clozapine) antipsychotic medications on NMDA-mediated n eurotransmission in the intact mouse. Also, marked differences in the ability of MK-801 to elicit popping behavior in inbred mouse strains s uggest that they differ in their popu lations of NMDA receptor complex es responsible for mediating this behavior. This latter observation co uld lend itself to the identification of specific genetic loci contrib uting to this behavior. In view of the ability of phencyclidine (PCP) to precipitate a schizophreniform psychosis and the action it shares w ith MK-801 on NMDA-mediated neurotransmission, the characterization of these genetic loci in mice may ii inform the search for human loci re sponsible fbr the susceptibility to ''PCP-psychosis'' and schizophreni a.