Effects of N-Methyl-D-aspartate (NMDA) Antagonists Ketamine, Methoxetamine, and Phencyclidine on the Odor Span Test of Working Memory in Rats

The glutamate hypothesis proposes that N-Methyl-D-aspartate (NMDA) receptor hypofunction underlies cognitive and perhaps other schizophrenic symptoms. The present study used the odor span task to assess the effects of NMDA antagonists on remembering multiple stimuli in rodents. This task uses an incrementing nonmatching-to-sample procedure in which responses to a new olfactory stimulus are reinforced on each trial, whereas responses to previously presented stimuli are not. NMDA antagonists have been associated with memory impairments in a variety of animal models; however, there are inconsistencies across different NMDA antagonists and tasks used. The current study compared the acute effects of phencyclidine (PCP), ketamine (KET), and the novel NMDA antagonist methoxetamine (MXE) on responding in the odor span task and a simple discrimination control task. PCP and MXE impaired odor span accuracy at doses that did not impair simple discrimination in most rats; however, the effects of KET were less selective. Within-session analyses indicated that the effects of PCP and MXE depended on the number of stimuli to remember, that is, impairment only occurred when the memory load was relatively high. These effects of PCP and MXE were consistent with the hypothesis that NMDA antagonists may interfere with working memory, but the basis for less selective results with KET are unclear. Public Health Significance The glutamate hypothesis of schizophrenia posits that NMDA receptor hypofunction may underlie some symptoms (particularly cognitive symptoms) of the disorder. The present study provided some support for this hypothesis in that we found that two NMDA receptor antagonists, phencyclidine and methoxetamine, selectively reduced memory capacity (ketamine effects were less selective) as measured by the odor span task. These results support the idea of the NMDA receptor as a potential target for new treatments for schizophrenia.