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 in the pathophysiologic mechanisms of several major neuropsychiatric disorders. Moreover, strategies for the pharmacologic manipulation of NMDA-mediated neural transmission have been discussed for the treatment of disorders as diverse as schizophrenia, seizures, stroke, and traumatic brain injury, MK-801, an uncompetitive allosteric antagonist of the NMDA receptor complex, was shown to antagonize electrically precipitated seizures in a dose-dependent manner and elicit popping behavior in mice. Changes in the ability of MK-801 to antagonize electrically precipitated seizures or elicit popping behavior caused by stress or pharmacologic 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 pharmacologic actions of an allosteric glycinergic intervention (i.e., milacemide), inhibitors of the "nitric oxide cascade" (i.e., 7-nitroindazole and methylene blue), and conventional (i.e., haloperidol) and atypical (i.e., clozapine) antipsychotic medications on NMDA-mediated neurotransmission in the intact mouse. Also, marked differences in the ability of MK-801 to elicit popping behavior in inbred mouse strains suggest that they differ in their populations of NMDA receptor complexes responsible for mediating this behavior. This latter observation could lend itself to the identification of specific genetic loci contributing to this behavior. In view of the ability of phencyclidine (PCP) to precipitate a schizophreniform psychosis and the action it shares with MK-801 on NMDA-mediated neurotransmission, the characterization of these genetic loci in mice may inform the search for human loci responsible for the susceptibility to "PCP-psychosis" and schizophrenia.
Deutsch
S I
SI
Department of Veterans Affairs Medical Center, Washington, DC 20422, USA.
Rosse
R B
RB
Mastropaolo
J
J
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate