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Exp Clin Psychopharmacol. Author manuscript; available in PMC 2019 February 01.
Published in final edited form as:
Exp Clin Psychopharmacol. 2018 February ; 26(1): 6–17. doi:10.1037/pha0000158.
Effects of NMDA antagonists ketamine, methoxetamine and
phencyclidine on the odor span test of working memory in rats
Michael J. Mathews1, Ralph N. Mead2, and Mark Galizio1
1Department
of Psychology, UNC Wilmington
2Department
of Chemistry, UNC Wilmington
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Abstract
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The glutamate hypothesis proposes that 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 non-matching-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, ketamine, and the novel NMDA antagonist
methoxetamine on responding in the odor span task and a simple discrimination control task.
Phencyclidine and methoxetamine impaired odor span accuracy at doses that did not impair simple
discrimination in most rats, however the effects of ketamine were less selective. Within-session
analyses indicated that the effects of phencyclidine and methoxetamine depended on the number
of stimuli to remember, i.e., impairment only occurred when the memory load was relatively high.
These effects of phencyclidine and methoxetamine were consistent with the hypothesis that
NMDA antagonists may interfere with working memory, but the basis for less selective results
with ketamine are unclear.
Keywords
NMDA antagonist; working memory; odor span task; ketamine; phencyclidine; methoxetamine
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The initial impetus for the NMDA hypofunction hypothesis of schizophrenia was the
observation that NMDA receptor antagonists like phencyclidine and ketamine produced
many of the symptoms that characterize the disorder in humans, including the full spectrum
of positive, negative and cognitive symptomatology (Merritt, McGuire & Egerton, 2013;
Moghaddam & Javitt, 2012). There has been particular interest in the translational value of
Corresponding author: Mark Galizio, PhD, Department of Psychology, UNC Wilmington, 601 S. College Rd., Wilmington, NC,
28403, galizio@uncw.edu, 910-962-3813. Ralph N. Mead, PhD, is at UNC Wilmington and Michael Mathews, MA, is now at West
Virginia University.
Some of the data reported in this article were presented at the Annual Meeting of the Society for Neuroscience, Chicago, IL October,
2015.
All authors contributed in significant ways to the paper and all have read and approved the ms.
None of the authors report any conflict of interest relevant to the present research.
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the hypothesis with respect to cognitive impairment (Gilmour et al., 2012). For example, the
effects of NMDA antagonists have been assessed in a variety of animal models of working
memory. However, results of these studies have provided mixed support for the hypothesis,
and suggest that whether impairment of working memory by NMDA antagonist is observed
depends on the nature of the task, task parameters, and the particular compound employed
(Bannerman, Rawlins, & Good, 2006; Dix et al., 2010; Gastambide et al., 2013; Gilmour et
al., 2009; Smith et al., 2011). One of the more promising tasks is the Odor Span Task (OST),
which was nominated as a benchmark procedure to model working memory capacity in
rodents by the CNTRICS group –Cognitive Neuroscience Treatment Research to Improve
Cognition in Schizophrenia—(Dudchenko, Talpos, Young & Baxter, 2013).
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The OST was originally developed as a way to study the neurobiology of working memory
for multiple stimuli by Dudchenko, Wood & Eichenbaum (2000). The procedure uses an
incrementing non-matching to sample task in which rats are presented with odors in a large
arena; each odor serves as a stimulus indicating reinforcer availability the first time it is
presented, but not during following presentations. For example, in the first trial one odor is
presented (a cup with scented sand or covered with a scented lid) in the arena and digging in
the sand or lid removal produces a food reinforcer. In the second trial, two stimuli are
presented– the odor from the first trial along with a novel odor. Now the odor from Trial 1
serves as the sample stimulus, as such, a response to the novel odor results in reinforcement.
With each subsequent trial, a new odor is presented along with comparison stimuli from any
of the previous trials and selection of the new odor is always reinforced. Thus, the number of
sample stimuli to remember increases across the session. The number of correct responses
until the first error (span) is one measure purported to reflect memory capacity in the OST
and percent correct plotted as a function of the number of odors to remember is another
(Dudchenko et al., 2000; Galizio, Deal, Hawkey & April, 2013).
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There is a growing literature using the OST to analyze drug effects that is beginning to
identify the neurobiological and pharmacological determinants of performance in this task.
OST performance is not affected by hippocampal lesions (Dudchenko et al., 2000) but is
impaired by inactivation of the medial prefrontal cortex (Davies, Molder, Greba & Howland,
2013). Consistent with the view that OST performance might be detect cognitive deficits in
animal models of schizophrenia, Murray, Davies, Molder & Howland (2017) observed span
deficits in the offspring of rats after maternal immune activation during pregnancy. Guided
by the NMDA hypofunction hypothesis of cognitive impairment in schizophrenia, much of
the early work on the behavioral pharmacology of the OST focused on NMDA antagonists.
As that hypothesis would predict, several studies have shown that these compounds impair
OST performances in rats. For example, the non-competitive NMDA antagonist MK-801
impaired span length and overall OST accuracy at doses that had no effect on a simple
discrimination task that controlled for drug effects on sensori-motor function, motivation and
reference memory (Galizio, et al., 2013; MacQueen, Bullard & Galizio, 2011). The
competitive NMDA antagonist CPP produced effects that were similarly selective to OST
performance (Davies, Greba & Howland, 2013; MacQueen, Dalrymple, Drobes & Diamond,
2016). Importantly, the effects of MK-801 were shown to depend on the number of stimuli
to remember. That is, effects were minimal when the memory load was low, but impairment
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of accuracy was accelerated as the number of odors to remember increased during the
session (Galizio et al., 2013; MacQueen, et al., 2011).
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Other amnestic drugs have been studied in the OST, but have produced less clear evidence of
working memory impairment. Rushforth, Allison, Wonnacott, and Shoaib (2010) found that
scopolamine decreased span length in rats at doses that did not increase latency to respond.
However, in a replication of that study that included the discrimination control condition,
scopolamine effects occurred only at doses that also impaired control performances (Galizio
et al., 2013). Benzodiazepines have produced selective impairments on OST performances
but the effects were quite different from those produced by NMDA antagonists. For
example, the effects of chlordiazepoxide were relatively weak and limited to span length
(Galizio et al., 2013). In contrast, flunitrazepam impaired OST accuracy at doses that spared
control performances, but these effects did not depend on the number of stimuli to remember
(Galizio, Mathews, Mason, Panoz-Brown, Prichard & Soto, 2017). Rather, the effects of
flunitrazepam appeared to involve a breakdown of the overall non-matching task. Thus, at
this point only NMDA antagonists have been shown to impair working memory in the OST.
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Although most of the current literature implicates NMDA receptor activity as a key
modulator of OST performance, a recent study found contrary results. Galizio et al. (2016)
found that the effects of the NMDA antagonist ketamine affected OST performances only at
doses that also impaired simple discrimination in 5/6 subjects. In most rats, effective doses
of ketamine produced a cessation of responding on both OST and simple discrimination
tasks. The discrepancy between findings of selective effects of MK-801 and CPP compared
with the non-selective effects of ketamine is puzzling, particularly as both MK-801 and
ketamine share a common mechanism as open channel blockers (Lodge & Mercier, 2015).
Ketamine is less potent and is a lower affinity channel blocker than MK-801 (Lodge &
Mercier, 2015; Monaghan, Irvine, Costa, Fang & Jane, 2012) which might account for the
differences in their effects on OST performance. However, a number of studies have also
observed differences between the behavioral effects of various uncompetitive NMDA
antagonists in a variety of tasks (Dix et al., 2010; Gastambide et al., 2013, Gilmour, et al.,
2009; Smith et al., 2011) and it seems important to determine the effects of different
compounds in the OST.
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Thus, one purpose of the present study was to extend the analysis of NMDA antagonists on
OST performance to two additional compounds: phencyclidine (PCP) and methoxetamine
(MXE). PCP is a potent channel blocker that produces schizophrenic-like symptoms in
humans and also was one of the key compounds that originally led to the NMDA
hypofunction hypothesis of schizophrenia (Merritt et al., 2013). MXE is a designer drug that
has recently emerged as an abuse problem in the United States and Europe in recent years
(Zanda, Fadda, Chiamulera, Fratta, & Fattore, 2016). Although MXE research is in early
stages, it does appear to act as an uncompetitive NMDA channel blocker (Roth et al., 2013)
and substitutes for ketamine in drug self-administration and drug discrimination procedures
(Mutti et al., 2016; Chiamulera, Armani, Mutti, & Fattore, 2016). No research has yet
assessed the effects of MXE using working memory tasks.
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A second purpose of the study was to replicate the effects of ketamine in the OST using a
more refined variation of the task. In the original version of the OST, the number of
comparison stimuli in the arena incremented along with the number of stimuli to remember
(Dudchenko et al., 2000). As this procedure results in a potential confound, our laboratory
adjusted the task to hold the number of comparison stimuli constant at five while continuing
to increase the memory load (Galizio et al., 2013; 2016; MacQueen et al., 2011). However,
the presence of even five different comparison stimuli in the arena might reduce the
sensitivity of the task to working memory effects by increasing the discrimination difficulty
and the need to inhibit responding. Perhaps potential amnestic effects of ketamine in the
Galizio et al., (2016) study were masked by other actions that led to disrupted performance
due to task complexity. In order to test this hypothesis, the present version of the OST used a
two-choice procedure in which each trial (after the first) presents one new odor (reinforced–
S+) and one previously presented negative comparison (S−). MacQueen et al. (2016) used a
two-choice OST and found it sensitive to the effects of CPP; our hypothesis was that a twochoice OST would show higher sensitivity to amnestic ketamine effects than the five-choice
procedure.
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Methods
Subjects
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Sixteen male Sprague-Dawley rats between 90 and 150 days old at the onset of the study
served as subjects. Rats were housed individually in Plexiglas cages measuring 34.5 cm L ×
18 cm W × 24.5 cm H and were maintained on a 12:12 reverse dark/light schedule with
artificial lighting initiated at 7 P.M. and turned off at 7 A.M. Subjects were allowed free
access to water in the home cage, but food (Purina Lab Diet 5001 Rodent Diet–PMI
Nutrition International, INC Brentwood, MO) was restricted to maintain 85% of free feeding
weight. Animal care as well as all aspects of the procedures were approved by the UNC
Wilmington IACUC.
Apparatus
A circular open-field arena (94 cm in diameter) surrounded by 32 cm high metal baffling
was used for this experiment. The floor of the arena included 18 holes, spaced 13.3 cm apart
in two circular arrangements in which 60 ml plastic cups were placed (see Figure 1). Each
arena was located in a small testing room with a video camera positioned in the ceiling for
digital recording of each session. White noise (70 dB) was presented for the duration of the
session.
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Stimuli
Plastic cups half full of sand were covered with plastic opaque scented lids. The lids were
scented with various odorants. These lids were odorized via storage in plastic containers
containing aromatic oils and spices as odorants (acai, allspice, anise, apple, banana, bay,
black walnut, bubblegum, caramel, caraway, carob, celery, cherry, chocolate, cinnamon,
clove, coconut, coriander, cumin, dill, fennel, fenugreek, garlic, ginger, honey, lilac, maple,
marjoram, marshmallow, mustard, nutmeg, onion, oregano, pecan, pine forest, pumpkin, root
beer, rosemary, sage, savory, spinach, sumac, thyme, watermelon) purchased from Nature’s
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Garden, McCormick, Sigma Aldrich, and Great American Spice Co. Lids were suspended
above oils or spices during storage, rather than directly in the odorants, so that the
concentration of odorant was relatively consistent across lids and were stored at least 3
weeks prior to initial use. Containers of spices and oils were refreshed every three to four
weeks. To control for scent marking on lids within session, each lid was replaced with one of
the same odor every time the scent was presented during a session.
Procedure
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OST Training—Sessions were conducted 5 days per week (Monday–Friday). Subjects
were first habituated to the apparatus, and hand shaped to remove a lid from a baited
stimulus cup. Rats were then trained on an incrementing non-match-to-sample procedure. In
this procedure, a novel odorant was presented during each trial along with odorants from
previous trials. Removal of the novel scented lid resulted in food reinforcement, while
removal of any previously presented lid did not. Initially, the number of cups in the arena
incremented on each trial, and errors (removal of a previously presented scented lid) resulted
in a reset—that is, on the following trial only one scented lid was present. After an average
of 11 days, the baseline OST schedule was implemented.
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Following initial OST training, rats began training on the 2-choice OST baseline procedure.
Two features of baseline OST training were different from that of initial training. First,
errors no longer resulted in resetting the stimulus arrangement to a single stimulus. Second,
following Trial 2 the number of comparison stimuli in the arena was held constant at two
(See Fig. 1): a new baited odor each trial (+) and an unbaited odor (−) which was randomly
selected from any of the previously presented odors (with the constraint that an odor was
never presented more than three times in a row). Figure 1 illustrates four typical OST trials
(OST1-OST4). During the first trial (OST1) only one cup is presented, covered by a lid
scented with odor A. Upon removal of lid A (A+), a sucrose pellet, which had been covered
by the lid, is available as food reinforcement (signified by the + symbol). In the second trial
(OST2), two odors are presented: scented lids A and B; as odor A has been previously
presented, there is no sucrose pellet available under lid A (signified by the – symbol). Odor
B is novel in this trial, thus removal of lid B will provide access to a sucrose pellet. Trial 3
(OST3) contains odors B and C, and as B has been previously presented, removal of lid B
will not produce a pellet. These three trials each use the previous positive (+) stimulus as the
negative (−) stimulus in the successive trial, however, any previously presented odor can
serve as a negative stimulus. This is illustrated in trial 4 (OST4), where odor A is presented
again as a negative stimulus, with the novel odor D. Figure 1 also contains an example of
two simple discrimination control (SDC) trials, SDC1 & SDC2, which were added once
subjects met a mastery criterion: two consecutive sessions with accuracy at 72% or greater.
Combined OST/SDC Baseline—SDC trials (See SDC1 & SDC2; Fig. 1) consisted of a
pair of scented lids. Unlike the OST, in SDC trials the same odor (X+) was consistently
baited across all SDC trials and sessions, while the alternative odor (Y−) was never baited.
This consistency is demonstrated in figure 1: X is presented with the + symbol and Y with
the – symbol in both SDC1 & SDC2. Although the pair of odors (X & Y) differed between
subjects, each pair remained constant for each subject (see Table 1) once SDC trials were
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introduced, and these odors were never presented as choices during OST trials. As task
demands were similar between the OST and SDC task, save for the increase in negative
comparison stimuli (number of stimuli to remember) in the OST, the SDC served to control
for drug effects on reference memory as well as non-mnemonic drug effects.
Initially, six SDC trials were presented following 25 OST trials. After rats responded with
100% accuracy to the 6 SDC trials while maintaining at least 72% accuracy in the OST
during one session, the SDC trials were pseudo-randomly interspersed throughout each
session during the following sessions (As shown in Fig. 1). SDC trials were spread across
the session so that the varying effects of drugs on performance over time could be captured.
Although interspersing the SDC trials among OST trials was expected to initially cause
some disruption of the odor span task, after a few sessions subjects readily learned to
discriminate between odors signaling the SDC task versus the OST and respond accordingly.
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Two additional control procedures were applied when the OST and SDC were combined.
First, a “no-bait” control procedure was added in six pseudo-randomly chosen OST trials per
session, one session per week. In these trials, neither stimulus cup contained a reinforcer, but
a sucrose pellet was placed in the S+ cup immediately following a correct response. This
control procedure allowed for verification that the odor of the lid, rather than the sucrose
pellet beneath, controlled responding. Second, one session per week included a fresh cup
control procedure. This procedure consisted of four pseudo-randomly chosen OST trials in
which the S- cup was replaced with a cup that had not been used previously in the session.
This control procedure allowed the experimenters to examine whether trace odors from the
stimulus cup, rather than the scented lid, affected OST accuracy. Table 1 details mean
percent correct across baseline, no bait, and fresh cup trials for each rat. Several subjects
(M22, M5, K10, L7, & L24) did not receive the fresh cup procedure as it was implemented
later in the experiment. Accurate responding was maintained during fresh cup and nonbaited sessions. This indicates that neither the scent of the sucrose pellet nor the scent of the
cup was likely responsible for accurate responding in the OST.
The combined OST and SDC tasks constituted the drug baseline. After meeting a stability
criterion for OST accuracy, which required that the mean difference in accuracy between the
most recent five sessions and the five preceding sessions was less than 10% of the grand
mean of those ten sessions, subjects began to receive injections. The number of training
sessions required ranged from 37 to 97 with an average of 54.7 sessions (Table 1). Following
this extensive training, rats maintained stable and high levels of accuracy on both the OST
and SDC task.
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Drugs
All drugs were dissolved in .09% saline solution and delivered in a volume of 1ml/kg. PCP
HCl (a generous gift from the NIDA drug supply program, RTP) was administered in doses
of 1.0, 3.0, 5.6, and 10.0 mg/kg and Ketamine HCl (Sigma) in doses of 1.0, 3.0, 5.6, 10.0,
18.0, 30.0, and 40.0 mg/kg. MXE HCl (Debora Labs, Copenhagen) was administered in
doses of 1.0, 3.0, 10.0, 18.0, 30.0 and 40.0 mg/kg. Because the provenance of MXE was
uncertain, the structure was verified using 1- and 2- dimensional Nuclear Magnetic
Resonance (NMR) spectroscopy, High Resolution Mass Spectrometry (HRMS), and
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comparison with the data in the current literature. NMR and LC/MS found no significant
organic impurity.
Drug Protocol
Intraperitoneal injections were administered 15 minutes prior to session start three days per
week. Saline was delivered Thursdays as an injection control, while active drug was
administered on Tuesdays and Fridays. Experimenters remained blind to the dose
administered. No injections were given Mondays or Wednesdays, which served as a
continuation of the baseline. Two or three determinations of a dose were given for each rat;
each dose in a set of determinations was administered prior to the second round of doses.
Some subjects received more than one drug, either in this study or in an experiment not
described here; for these animals a two-week washout period intervened before the next drug
study began.
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Data Analysis
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Accuracy was determined by the first response in each trial for both OST and SDC trials. If
a subject failed to respond within 2 minutes, the trial was scored as an omission; omitted
trials were not included in the percent correct calculation. Omitted trials were repeated with
presentation of only the positive stimulus, and sessions were terminated following either 3
consecutive or 6 total omissions. Consecutive correct measures included span and longest
run. Span was defined by number of correct responses made until the first error in the
session, excluding Trial 1 as there was no comparison stimulus. Longest run was determined
as the greatest number of correct consecutive responses in the session. This measure
provided more information than span, as a rat could make an error on Trial 2 resulting in a
span of 1. However, the rat could then respond correctly on trials 3–20, resulting in a longest
run of 17. Latencies for each trial were measured in seconds from the placement of the rat in
the arena until a response was made.
Video recordings of ten randomly selected sessions were scored by a blind observer to
determine inter-rater reliability (IRR). IRR was calculated by comparing scores of the
observer with scores of the experimenter from the chosen session. The two raters agreed on
98% of the chosen trials, which indicated a high reliability of the operational definition of
the lid removal response.
Results
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Mean effects of PCP on the main dependent variables are displayed in Figure 2. The top
panel shows percent correct as a function of dose for the OST (closed circles) and SDC task
(open circles). Under control conditions (saline), accuracy for the OST was around 90%,
while accuracy for the SDC task was near 100%. PCP produced dose-dependent impairment
in accuracy on both tasks. At the 3.0 mg/kg dose, OST accuracy was slightly decreased and
then more clearly impaired at the 5.6 mg/kg dose. In contrast, at both of these doses,
accuracy on the SDC task was relatively unaffected, remaining above 90%. Thus, the effects
of the 5.6 mg/kg dose were selective to the OST. Percent omissions is indicated by the bars
on the right axis of the graph, representing trials in which a failure to respond to either
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stimulus within two minutes occurred. At the 5.6 mg/kg dose occasional omissions were
observed, whereas at the 10.0 mg/kg dose behavior was grossly affected, resulting in over
70% omissions. Statistical analysis used a within-subject ANOVA with dose (4 levels—the
10 mg dose was omitted from the analysis due to the high number of omissions) and task
(OST vs. SDC) as the main variables. The effects of PCP were verified by a significant dose
x task interaction: F (3, 15)=6.95, p<.05, with main effects of dose [F(3,15)=5.16, p<.05]
and task [F(3,15)=23.50, p<.05]. Fisher’s LSD tests revealed that the 5.6 mg/kg dose
significantly reduced OST accuracy below saline levels (p<.05) but that SDC accuracy was
unaffected (p>.05). Thus, PCP produced effects that were selective to OST performances at
this dose. Figure 2 (middle panel) also shows that under control conditions, mean spans
(closed circles) ranged from 7−11 odors, while longest runs (open circles) were higher at
12−15 consecutively correct responses. Span and longest run were each statistically
analyzed using one-way within-subject ANOVAs. Both span [F (4, 20)= 5.92, p<.05] and
longest run [F (4, 20)= 21.70, p<.05] were dose-dependently decreased by PCP
administration. Fisher’s LSD tests revealed span was significantly lower at the 10.0mg/kg
dose compared to saline (p<.05) and longest run was significantly below saline levels at the
5.6 and 10.0 mg/kg dose (p<.05). Latencies to respond to (Fig. 2, bottom panel) increased at
the 5.6 mg/kg dose [F (3, 15)=7.01, p<.05]. The selective effects of PCP were also evident in
an individual subject analysis (Figure 3). In these graphs, mean percent correct for the OST
(closed circles) and SDC task (open circles) for each rat is plotted as a function of PCP dose.
Five of the six rats, (M5, N11, N33, P17 and P25) showed selective effects of PCP at the 5.6
mg/kg dose with decreased OST accuracy but minimal effects on SDC performances. Rat
M10 (top right panel) was the only subject in which no selective effects were evident.
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The effects of MXE on the main dependent variables are shown in Figure 4. Under the saline
control condition, accuracies were around 85% for the OST and 95% for the SDC task.
MXE dose-dependently impaired accuracy on both tasks, however this did not occur until
the 18.0 and 30.0 mg/kg doses. The data were analyzed statistically by a within-subject
ANOVA with dose (6 levels) and task (OST vs. SDC) as the main variables. A main effect of
dose was found [F (5, 25)= 5.93, p<.05]. There was not a significant main effect for task [F
(5, 25)= 3.27, p>.05], nor a significant interaction [F (5, 25)= 0.4, p>.05] Fisher’s LSD tests
revealed a significant overall difference between saline and the 30.0 mg/kg dose. Percent
omissions (bars on right side) also increased to around 40% at the 18.0 and 30.0 mg/kg
doses. The high doses disrupted responding in both tasks, thus the effect appears nonselective. Consistent with the decreases in overall accuracy, mean spans (closed circles) and
longest runs (open circles) were also reduced at the higher doses of MXE (Fig. 4, middle
panel). Both span [F (5, 25)= 3.30, p<.05] and longest run [F (5, 25)= 11.30, p<.05] were
significantly decreased by MXE administration dose-dependently with Fisher’s LSD tests
revealing that both measures were significantly below saline levels only at 30.0 mg/kg (p<.
05). Latencies to respond to both tasks (Fig. 4, bottom panel) were somewhat elevated at the
higher doses [F (5, 25)= 3.68, p<.05]. The group data did not appear to show a selective
effect of MXE, as responding on both tasks was affected similarly, and impairment only
occurred at doses in which high rates of omissions were observed.
However, the individual subject data for the rats administered MXE (Fig. 5) provide a
somewhat more complex picture of the effects of MXE on responding. Three subjects
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showed a clear selective effect of MXE on OST percent correct: O7, P3, and M22 (right
three panels). Rat O7 (top left panel) was unaffected by the lower doses of MXE, but at the
18.0 mg/kg dose, accuracy declined on the OST while remaining at 100% for the SDC task.
For P3, OST accuracy decreased across the 10.0, 18.0 and 30.0 mg/kg doses, while accuracy
on the SDC task was unaffected. Subject M22’s percent correct was decreased under both
the 18.0 and 30.0 mg/kg doses, while responding on the SDC task remained at 100%
accuracy. Two additional subjects (P24 and P26) also showed selective effects of lesser
magnitude. In the case of P24, a small decrease in OST, but not SDC, accuracy was observed
at the 10 mg/kg dose. P26 showed a consistent drop in OST accuracy at the 10 and 18 mg/kg
doses, but SDC was also slightly impaired at these doses. Finally, Rat P18 (top left panel)
showed no effects of MXE until the 18.0 and 30.0 mg/kg doses which resulted in complete
omissions.
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In sum, MXE disrupted accuracies on the OST and SDC and reduced spans and longest
runs. Although the group data analysis failed to reveal evidence of selective effects on the
OST, the individual subject data for the MXE group provided some evidence of selectively
in five of the six rats. The doses at which responding was disrupted were variable across the
six subjects in the MXE study. This differential sensitivity to MXE effects may explain why
the mean data appeared to be non-selective whereas individual rats in fact did show selective
effects at some doses.
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The top panel of Figure 6 shows the effects of ketamine (KET) on percent correct. KET
reduced accuracy at the 30.0 mg/kg dose, [F (5, 25)= 6.34, p<.05] which also increased
omissions. The 30.0 mg/kg dose disrupted responding in both tasks, thus the effect appears
non-selective. Mean spans [F (5, 25)= 6.34, p<.05] and longest runs [F (5, 25)= 5.36, p<.05]
were also reduced at the 30 mg/kg dose (Fig. 6, middle panel). No significant effects were
obtained for response latencies (Fig. 6, bottom panel). In sum, the group data did not show a
selective effect of KET, as accuracy on both tasks was maintained across doses until the 30
mg/kg dose, at which high rates of omissions were observed in both OST and SDC tasks.
Individual subject data for the KET group (Fig. 7) generally support the mean data. All
subjects maintained SDC accuracy similar to saline levels, and most did not show declines in
OST accuracy below saline levels at any KET dose. Four animals (M5, L24, K10, L7) were
nearly unaffected by ketamine until doses were reached which caused substantial omissions.
However, one subject (P17) did show a clearly selective effect with a reliable drop in OST,
but not SDC, accuracy at the 30.0 mg/kg dose. Overall, effects of KET were generally
limited to doses that disrupted overall responding with the selective effects in P17 standing
as the exception.
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Although PCP selectively impaired accuracy on the OST, a within-session analysis was used
to determine whether the effects of PCP depended on the number of odors to remember.
Figure 8 shows such an analysis comparing the selective dose (5.6 mg/kg) of PCP (open
triangles) to the saline control (closed triangles) across the OST (3 bins of 8 trials–left half
of x-axis) and the SDC trials (three bins of two trials–right half of x-axis) for the five
animals that showed selective effects. Note that accuracy decreased only slightly across the
session under saline conditions. Indeed, during the final eight trials with 17–24 odors to
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remember, OST accuracy remained above 80% after saline. However, there was a sharp drop
in OST accuracy as the number of stimuli to remember increased under PCP. Accuracy was
only slightly lower than control in the first bin (1–8 odors), but dropped to about 60%
correct when the memory load was 9–24 stimuli. ANOVA with drug (2 levels: Saline vs.
PCP) and bin (3 levels: 1 vs. 2 vs. 3) as the main variables confirmed these conclusions with
a significant dose X bin interaction [F (1,4)=7.10, p<.05]. Note that accuracy on SDC trials
remained high throughout the session with or without PCP.
Author Manuscript
Within-session analysis for MXE was complicated by the individual differences in
sensitivity. Due to this variability, MXE within-session data (Fig. 9) were analyzed using a
best dose analysis which compared the means of the most selective dose for the five rats that
showed selective effects (open triangles) with saline (closed triangles) across the session.
The doses used were 10.0 (P24 & P26), 18.0 (O7), and 30.0 mg/kg (M22 & P3). The results
were similar to PCP in that there was very little decline in accuracy across the session under
saline conditions, and MXE-induced impairment of accuracy was most evident when the
memory load was fairly high (9–24 stimuli). Factorial ANOVA revealed a significant
interaction of drug and bins of trials [F (1,4)= 8.73, p<.05). Accuracy on the SDC trials
remained relatively high across the session.
Discussion
Author Manuscript
All three NMDA antagonists reduced span length, longest run, and accuracy in a dosedependent fashion, but the three compounds differed in the extent to which the effects were
selective to the OST. At high doses, all three drugs disrupted SDC as well as OST
responding with frequent response omissions. At moderate doses, both PCP and MXE
produced effects that were selective to the OST and were consistent with an interpretation in
terms of impaired within-session or working memory. KET effects were much less selective
to the OST, and appear to have been based on non-amnestic disruption of performance in
most rats tested.
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PCP produced the most selective effects as OST accuracy and longest run were significantly
decreased (and decreases in span length approached significance) at the 5.6 mg/kg dose
which had no effect on SDC accuracy. Three of the subjects did show an increase in
omissions at this dose and response latency also increased, suggesting that some general task
disruption was occurring. That said, the observed change in OST accuracy approached a
15% decline while SDC performance remained nearly perfect at the 5.6 mg/kg dose
suggesting that the PCP effects were selective to the OST at this dose. This observation was
corroborated by the within-session analysis of PCP effects, which revealed that when
memory load was 1–8 stimuli, 5.6 mg/kg PCP had little effect on accuracy compared to
saline. However, as the number of stimuli to remember increased from 9–23 stimuli,
accuracy declined sharply under 5.6 mg/kg PCP, whereas only a slight decline was observed
in the saline conditions. In short, the effects of PCP depended on the number of stimuli to
remember.
Overall, MXE effects were similar to those of PCP, but individual rats varied considerably in
their sensitivity to the drug. Some subjects showed selective effects of MXE at 18 mg/kg
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(O7, P3) or 30 mg/kg (M22) while both OST and SDC performance was disrupted in the
other three rats at these doses. A best-dose analysis used to detect within session effects
produced a function resembling that for PCP with very little MXE effect when the memory
load was 1–8 stimuli, but substantial impairment relative to saline as the number of stimuli
to remember increased throughout the session.
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Finally, ketamine effects were somewhat different than the other compounds as it produced
very little effect on accuracy of either OST or SDC responding until high doses were
reached that disrupted responding on both tasks and increased omissions in most subjects.
One subject (P17) did show a selective effect with reduced OST but not SDC accuracy at the
30 mg/kg dose, but overall ketamine effects were clearly less selective than MXE or PCP.
These findings replicate those of a previous study from our laboratory, which used a fivechoice OST (Galizio et al., 2016). In that study, as in the present one, only one out of six rats
showed a selective effect of ketamine on the OST. Thus, the limited selectivity of ketamine
on OST responding in Galizio et al. (2016) was not related to the number of comparison
stimuli—rather ketamine appears to produce relatively non-selective effects with the both
the five-choice and the present two-choice versions of the OST.
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The present study was the first to determine the effects of PCP and MXE using the OST. The
effects of PCP on OST observed in the present study closely resembled previous results with
NMDA antagonists MK-801 and CPP (Davies, et al., 2013; Galizio, et al., 2013; MacQueen
et al., 2011; 2016). In those studies NMDA antagonists selectively impaired OST accuracy
at doses that did not affect other aspects of performance (e.g., SDC accuracy). One
qualification with respect to PCP is that although the 5.6 mg/kg dose reliably produced
selective impairment of OST accuracy, this dose also resulted in some global impairment
(increased omissions and response latency) in several animals. Still, an interpretation of PCP
disruption of OST accuracy in terms of amnestic effects seems appropriate. Interpretation of
the MXE results is more complex. If the group mean data alone were considered, the
conclusion would be the MXE did not produce selective effects; only when individual
subject dose-response functions were analyzed was evidence of selective actions observed.
Group statistical analysis using a best-dose procedure did show selectivity and supported the
observation that MXE effects depended on the number of stimuli to remember. One caveat
here is that best-dose analyses are potentially biased in the direction of showing positive
effects (Soto, Dallery, Ator, & Katz, 2013). Very little research has been conducted with
MXE and further studies will be needed to determine the extent to which MXE selectively
impairs within-session/working memory.
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The present study provided mixed support for the hypothesis that NMDA hypofunction is
associated with reduced memory capacity. On the one hand, the selective effects and
memory-load dependent effects of PCP and MXE obtained in the present study were
consistent. These findings, combined with those of previous studies that studied MK-801
and CPP on OST performances, provide strong support for the hypothesis. However, the
relatively non-selective effects of ketamine were inconsistent. Why would ketamine result in
such different effects than other NMDA antagonists? As noted previously, other researchers
have observed differences between various NMDA antagonists in a variety of behavioral
tasks, and it is unclear whether these may reflect pharmacokinetic or pharmacodynamic
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differences across compounds (Dix et al., 2010; Gastambide et al., 2009; 2013, Smith et al.,
2011). Using a somewhat different procedure—the self-ordered spatial search task—to
assess memory capacity, Taffe, Davis, Gutierrez & Gold (2002) found that ketamine did
produce selective impairments in rhesus monkeys that depended on the number of stimuli to
remember. Thus, it is possible that a species difference in sensitivity to ketamine may be
involved. It has also been noted that binding site affinity varies across NMDA antagonists.
Ranking the uncompetitive antagonists in terms of affinity, MK-801 > PCP > MXE > S-(+)KET (Wong et al., 1986; Halberstadt, Slepak, Hyun, Buell, & Powell, 2016). This hierarchy
might account for the findings of ketamine’s limited selectively on OST performance.
Perhaps some affinity threshold is required to produce selective effects on working memory
in the OST. Studies with additional compounds (e.g., lower affinity compounds such as
memantine) are needed to test such a hypothesis.
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Finally, it should be added that although results from the OST are generally interpreted in
terms of within-session or working memory, the translational significance of such
interpretations remain to be determined. Certainly numerous studies, including the present
one, have shown functional differences between the within-session remembering involved in
the OST relative to reference memory tasks like the SDC. However, the relationship between
the within-session memory of the OST and human working memory tasks remains puzzling.
Consider that human memory span is highly limited (Gathercole, 2009). In contrast, very
little decline in accuracy was observed in the present study even as the memory load reached
16–24 odors. Indeed, the upper limit on rat’s capacity to remember odors has not been
reached with previous OST studies showing above chance memory for 70–100 different
odors (April, Bruce, & Galizio, 2013; Bratch et al., 2016). It has been suggested that
performance in the OST is best conceptualized as a form of short-term episodic-like memory
(Branch et al., 2014; Panoz-Brown, Corbin, Dalecki et al, 2016) and if this hypothesis is
confirmed, it would have implications for the interpretation of the effects of NMDA
antagonists as well.
Acknowledgments
This research was supported in part by NIDA grant DA029252, Mark Galizio, PI. Only financial support was
provided by NIDA.
The authors thank Katrina Gobenciong, Angela Goolsby, Chloe Myers, Danielle Panoz-Brown, and Ashley
Prichard who assisted in data collection and analysis.
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Public Significance Statement
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.
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Figure 1.
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Examples of OST and SDC trials. Each large circle represents an individual trial; OST1OST4 represent OST trials 1-4 while SDC1 and SDC2 represent interspersed SDC trials.
The small circles represent 18 possible stimulus locations in the apparatus. A letter
represents a specific odor in a location; letters A, 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) for OST2, 2 (A, B) for OST3, 3
(A, B, C) for OST4, and so on. During all SDC trials, selection of X (X+) always produced a
sucrose pellet, while a selection of Y (Y−) did not.
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Figure 2.
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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.
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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.
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Figure 4.
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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.
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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.
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Figure 6.
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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.
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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.
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Figure 8.
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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.
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Figure 9.
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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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Table 1
Number of Sessions
Percent Correct
Exp Clin Psychopharmacol. Author manuscript; available in PMC 2019 February 01.
Rat
OST
OST/SDC
Total
Baseline
No Bait
Fresh Cup
Drug
SDC odors (+,−)
O7
7
65
72
82.33%
93.00%
94.00%
MXE
Pumpkin, Honey
M22
10
27
37
96.89%
88.98%
–
MXE
Marshmallow, Pine Forest
P3
11
86
97
81.76%
84.00%
83.33%
MXE
Watermelon, Black Walnut
P18
13
24
37
78.00%
81.00%
67.00%
MXE
Maple, Acai
P24
7
36
43
82.00%
86.00%
89.00%
MXE
Caramel, Apple
P26
20
33
53
79.81%
87.00%
77.00%
MXE
Banana, Root beer
M10
10
54
64
92.00%
100.00%
87.50%
PCP
Lilac, Honeydew
N11
7
81
88
87.38%
89.00%
86.00%
PCP
Pecan, Pine Forest
N33
7
30
37
85.20%
90.00%
100.00%
PCP
Marshmallow, Pine Forest
P25
9
30
39
87.73%
88.00%
90.00%
PCP
Pumpkin, Honey
P17
15
31
46
79.14%
74.00%
78.00%
PCP, KET
Pecan, Pine Forest
M5
10
33
43
88.33%
90.00%
–
PCP, KET
Chocolate, Bubblegum
K10
11
56
67
86.15%
74.35%
–
KET
Black Walnut, Champagne
L7
11
24
35
93.00%
91.67%
–
KET
Coconut, Lavender
L24
13
28
41
89.00%
89.28%
–
KET
Rum, Maple
N36
16
27
43
92.00%
94.74%
81.58%
KET
Apple, Banana
Mathews et al.
Training, Performance Under Baseline and Control Conditions and SDC Odorants
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