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.2018 Feb;26(1):6-17.
doi: 10.1037/pha0000158.

Effects of N-Methyl-D-aspartate (NMDA) antagonists ketamine, methoxetamine, and phencyclidine on the odor span test of working memory in rats

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Effects of N-Methyl-D-aspartate (NMDA) antagonists ketamine, methoxetamine, and phencyclidine on the odor span test of working memory in rats

Michael J Mathews et al. Exp Clin Psychopharmacol.2018 Feb.

Abstract

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. (PsycINFO Database Record

(c) 2018 APA, all rights reserved).

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Conflict of interest statement

None of the authors report any conflict of interest relevant to the present research.

Figures

Figure 1
Figure 1
Examples of OST and SDC trials. Each large circle represents an individual trial;OST1-OST4 represent OST trials 1-4 whileSDC1 andSDC2 represent interspersed SDC trials. The small circles represent 18 possible stimulus locations in the apparatus. A letter represents a specific odor in a location; lettersA, B, C, D, X, &Y indicate different odor stimuli (e.g.A= apple,B= banana). A plus sign next to a letter (e.g.A+) indicates that selection of that stimulus (A) would produce a sucrose pellet. A minus (e.g.B−) indicates that no pellet is available for selection of that odor (B). Notice that possible negative stimuli increase as OST trials increment: 1 possible negative (A) forOST2, 2 (A, B) forOST3, 3 (A, B, C) forOST4, and so on. During all SDC trials, selection of X (X+) always produced a sucrose pellet, while a selection of Y (Y−) did not.
Figure 2
Figure 2
Means for percent correct, consecutive correct, and latency for the PCP group.Top panel shows the effects of PCP on percent correct (circles) and omissions (bars) for the OST (closed circles, dark bars) and SDC task (open circles, light bars).Middle panel shows span (closed circles) and longest run (open circles).Bottom panel shows latency to first response for OST (closed circles) and SDC task (open circles).Vertical lines indicate SEM.
Figure 3
Figure 3
Individual subject graphs show the effects of PCP on percent correct (circles) and omissions (bars) for the OST (closed circles, dark bars) and SDC task (open circles, light bars).Vertical lines plotted for saline means indicate SEM.
Figure 4
Figure 4
Means for percent correct, consecutive correct, and latency for the MXE group.Top panel shows the effects of MXE on percent correct (circles) and omissions (bars) for the OST (closed circles, dark bars) and SDC task (open circles, light bars).Middle panel shows span (closed circles) and longest run (open circles).Bottom panel shows latency to first response for OST (closed circles) and SDC task (open circles).Vertical lines indicate SEM.
Figure 5
Figure 5
Individual subject graphs show the effects of MXE on percent correct (circles) and omissions (bars) for the OST (closed circles, dark bars) and SDC task (open circles, light bars). Vertical lines plotted for saline means indicate SEM.
Figure 6
Figure 6
Means for percent correct, consecutive correct, and latency for the KET group.Top panel shows the effects of KET on percent correct (circles) and omissions (bars) for the OST (closed circles, dark bars) and SDC task (open circles, light bars).Middle panel shows span (closed circles) and longest run (open circles).Bottom panel shows latency to first response for OST (closed circles) and SDC task (open circles).Vertical lines indicate SEM.
Figure 7
Figure 7
Individual subject graphs show the effects of KET on percent correct (circles) and omissions (bars) for the OST (closed circles, dark bars) and SDC task (open circles, light bars). Vertical lines plotted for saline means indicate SEM.
Figure 8
Figure 8
Within session graphs show the effects of 5.6 mg/kg PCP (open triangles) and Saline (closed triangles) on OST and SDC percent correct across the session in bins of 8 for the OST and 2 for the SDC.Vertical lines indicate SEM. Note that N = 5—P5 not included in this figure.
Figure 9
Figure 9
Group within session graphs show the effects of the selective dose of MXE for each rat (open triangles) and Saline (closed triangles) on OST percent correct across the session (bins of 8 trials) and the 6 SDC trials (bins of 2).Vertical lines indicate SEM. Note that N = 5—P18 not included in this figure.
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