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

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

Successive incrementing non‐matching‐to‐samples in rats: An automated version of the odor span task

“…In the successive arrangement, the proportion of responses to S+/S‐ is the critical measure. However, span can actually be a misleading measure in OST studies; unlike human working memory tasks such as the digit span, rats often perform with high accuracy after their first error (Galizio et al, 2013; 2016; Mathews et al, 2018). In sum, the absence of a span measure should not be viewed as a liability of the successive incrementing NMTS procedure.…”

“…The OST has become widely used in behavioral pharmacology and neuroscience and, following the interpretation of Dudchenko et al (2000), is often represented as providing a rodent model of working memory capacity (e.g., Bratch et al, 2016; Cui et al, 2011; Davies et al, 2017; DeFalco et al, 2019; Rushforth et al, 2010; 2011; Young et al, 2007). In support of this interpretation are findings that accuracy declines as the number of odors to remember increases and that this decline occurs even when the number of comparison choices is held constant across the session (Galizio et al, 2013; MacQueen et al, 2011; Mathews et al, 2018). Indeed, the OST has been considered to be a benchmark procedure to study working memory capacity in rodents by the CNTRICS group (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) and may be useful as a model for a variety of pathologies (Dudchenko et al, 2013; MacQueen et al, 2018).…”

MiR-185-3p mimic promotes the chemosensitivity of CRC cells via AQP5

“…Drug resistance remains an obstacle in cancer treatment. Though multiple mechanisms underlying drug resistance in cancers, such as improved DNA repair capacity, 1 defects in the DNA damage response, 2,3 anti-apoptosis, 4 pro-migration, 5 pro-proliferation effects, 6 autophagy, 7 tumor-associated compensatory pathways, 8 and changes in drug transport, 9 have been proposed, the exact mechanism of drug resistance in cancer is highly complex and has not been fully understood yet. Therefore, discoveries of new drug sensitivity-associated targets and effective drug combinations are considered as effective and promising strategies for improving the survival rate of cancer patients.…”

Effects of NMDA antagonist dizocilpine (MK-801) are modulated by the number of distractor stimuli in the rodent odor span task of working memory

“…Interestingly, these effects generally depend on the number of stimuli to remember. That is, effects were minimal when the memory load was low, but impairment of accuracy accelerated as the number of odors to remember increased during the session (Galizio et al, 2013;MacQueen et al, 2011;Mathews et al, 2018). In summary, findings from multiple laboratories have converged to find that NMDA antagonists interfere with memory capacity in the OST.…”

“…In early work from our laboratory, we found that the noncompetitive NMDA antagonist dizocilpine/MK-801 (DZP) impaired span length and overall OST accuracy at doses that had no effect on a simple discrimination task that controlled for drug effects on sensorimotor function, motivation, and reference memory (Galizio et al, 2013;MacQueen et al, 2011). More recently we found that two additional non-competitive NMDA antagonists, phencyclidine (PCP) and methoxetamine (MXE), selectively impaired OST accuracy, although the low-efficacy NMDA antagonist ketamine was less selective (Galizio et al, 2016;Mathews, Mead, & Galizio, 2018). Other laboratories have shown that the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) produced effects that were similarly selective to OST performance, as did the GluN2B-selective antagonist Ro 256981 (Davies et al, 2013(Davies et al, , 2017MacQueen, Dalrymple, Drobes & Diamond, 2016).…”