Systemic NMDA antagonist CGP-37849 produces non-specific impairment in a working memory task: The effect does not resemble those of AP5 and of lesions of the hippocampus or fornix

The N-methyl-D-aspartate (NMDA) receptor antagonist CGP-37849 (D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid), administered i.p. (2.0 and 4.0 mg/kg), impaired rats' performance in a delayed matching-to-sample working memory task. This task is sensitive to hippocampal/fornix lesions or intracerebroventricular (i.c.v.) administration of another NMDA antagonist, AP5 (2-amino-5-phosphono-pentanoic acid) in a stimulus-specific manner: the highest impairment when simple stimuli are used repeatedly; moderate impairment when complex stimuli are used repeatedly; and no impairment when complex stimuli are used in a pseudo-trial-unique fashion. The effect of CGP-37849, unlike those of surgical lesions and of AP5, was not stimulus-specific and therefore cannot be solely attributed to blockade of NMDA-dependent long-term potentiation (LTP) in the hippocampus. We infer that systemic administration of NMDA antagonists may affect a broad range of anatomical structures thereby interfering with other neural mechanisms of memory and motor performance.