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 Previous Article
Volume 17, Number 8,
Issue of April 15, 1997
pp. 2921-2927
Copyright ©1997 Society for Neuroscience
Activation of Glutamatergic Neurotransmission by Ketamine: A
Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic
and Cognitive Disruptions Associated with the Prefrontal Cortex
Bita Moghaddam,
Barbara Adams,
Anita Verma, and
Darron Daly
Department of Psychiatry, Yale University School of Medicine, VA
Medical Center 116A/2, West Haven, Connecticut 06516
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- CONCLUSIONS
- FOOTNOTES
- REFERENCES
ABSTRACT 
Subanesthetic doses of ketamine, a noncompetitive NMDA
receptor antagonist, impair prefrontal cortex (PFC) function in the rat
and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that
ketamine may impair PFC function in part by interacting with dopamine
neurotransmission in this region. This study sought to determine the
mechanism by which ketamine may disrupt dopaminergic neurotransmission
in, and cognitive functions associated with, the PFC. A thorough
dose-response study using microdialysis in conscious rats indicated
that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate
outflow in the PFC, suggesting that at these doses ketamine may
increase glutamatergic neurotransmission in the PFC at non-NMDA
glutamate receptors. An anesthetic dose of ketamine (200 mg/kg)
decreased, and an intermediate dose of 50 mg/kg did not affect,
glutamate levels. Ketamine, at 30 mg/kg, also increased the release of
dopamine in the PFC. This increase was blocked by intra-PFC application
of the AMPA/kainate receptor antagonist,
6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of
spatial delayed alternation in the rodent, a PFC-sensitive cognitive
task, was ameliorated by systemic pretreatment with AMPA/kainate
receptor antagonist LY293558. These findings suggest that ketamine may
disrupt dopaminergic neurotransmission in the PFC as well as cognitive
functions associated with this region, in part, by increasing the
release of glutamate, thereby stimulating postsynaptic
non-NMDA glutamate receptors.
Key words:
microdialysis;
phencyclidine;
schizophrenia;
working
memory;
antipsychotic drugs;
AMPA receptors
INTRODUCTION
Recent clinical trials with ketamine, a
noncompetitive antagonist of the NMDA receptor (Thomson et al., 1985 ),
have demonstrated that subanesthetic doses of this drug exacerbate
preexisting symptoms of schizophrenia (Lahti et al., 1995a,b) and
produce behaviors in healthy individuals that bear a resemblance to a
broad range of symptoms associated with schizophrenia, including
impaired performance in psychological tests sensitive to prefrontal
cortex (PFC) function (Ghoneim et al., 1985; Oye et al., 1992; Krystal et al., 1994; Malhorta et al., 1996). In agreement with clinical studies, basic findings indicate that subanesthetic doses of ketamine and other noncompetitive NMDA receptor antagonists produce deficits in
acquisition and performance of cognitive tasks, including those that
are sensitive to the functional integrity of the PFC (Danysz et al.,
1988; Hauber and Schmidt, 1989; Heale and Harley, 1990; Parada-Turska
and Turski, 1990; Wesierska et al., 1990; Hauber, 1993; Verma and
Moghaddam, 1996). These actions of ketamine are similar to those
observed decades ago with phencyclidine (Luby et al., 1959; Davies and
Beech, 1960; Bakker and Amini, 1961), which led to the "phencyclidine
model of schizophrenia" and, more recently, to several glutamate- and
NMDA-related hypotheses of schizophrenia (Kim et al., 1980; Deakin et
al., 1989; Wachtel and Turski, 1990; Javitt and Zukin, 1991; Ulas and
Cotman, 1993; Olney and Farber, 1995; Akbarian et al., 1996; Coyle,
1996).
Although the behavioral deficits that are produced by ketamine
(and PCP) suggest a role for the NMDA receptor in the etiology of
schizophrenia, several lines of evidence have pointed to a dysfunctional dopamine system (Matthysse, 1973; Angrist et al., 1974;
Snyder et al., 1974; Seeman et al., 1976). Interestingly, dopamine
neurotransmission contributes to the behavioral deficits produced by
low doses of ketamine because dopamine D2 receptor antagonists
ameliorate ketamine-induced impairment of some PFC-dependent functions
in humans and in the rodent (Krystal et al., 1995; Verma and Moghaddam,
1996). Furthermore, low doses of NMDA receptor antagonists, including
ketamine and PCP, preferentially increase dopamine release in the PFC
(Rao et al., 1989; Wedzony, et al., 1993; Hondo et al., 1994; Verma and
Moghaddam, 1996).
At high doses, ketamine and PCP are known to interfere with the
function of dopamine uptake sites (Smith et al., 1981); however, the
mechanism for their dopamine release-activating properties at low doses
remains unclear. Recent biochemical studies have indicated that NMDA
receptor antagonists may increase the release of endogenous excitatory
amino acids, glutamate, and aspartate (Bustos et al., 1992; Liu and
Moghaddam, 1995). This increase may then activate glutamatergic
neurotransmission at non-NMDA receptors, including AMPA and kainate
receptors. Recent studies from our laboratory have indicated that
stimulation of AMPA or kainate receptors potently increases the release
of dopamine in the PFC (Jedema and Moghaddam, 1996).
The present study was performed to test the hypothesis that ketamine
increases dopamine neurotransmission in the PFC and disrupts cognitive
functions associated with this region by activation of
glutamatergic neurotransmission at non-NMDA receptors. First, a
thorough dose-response study on the effect of ketamine on the outflow
of Glu in the PFC was performed using intracerebral microdialysis in
the awake rat. Second, the effect of a subanesthetic dose of ketamine
on the release of dopamine in the PFC and whether this effect is
produced by activation of non-NMDA receptors in the PFC were examined.
Finally, the effect of systemic pretreatment with a non-NMDA receptor
antagonist on ketamine-induced impairment of a PFC-related behavioral
paradigm and activation of dopamine release in this region was
examined. To evaluate the previous reports on the regional selectivity
of ketamine, some of the microdialysis experiments mentioned above were
also performed in the striatum.
MATERIALS AND METHODS
Animal preparation. Animal use procedures were in
accordance with the NIH Guide for the Care and Use of Laboratory
Animals and were approved by the Yale University Animal Care and
Use Committee. Microdialysis probes were implanted while rats were
under halothane anesthesia. Animals were placed in a stereotaxic frame
with blunt ear bars, and a small incision (3-5 mm) was made in the
skin over the skull. The wound margin was infiltrated with lidocaine,
and holes were drilled for skull screws and concentric microdialysis probes aimed (bilaterally) at the prefrontal cortex (anteroposterior, 3.0; lateral, 0.8; ventral, 5.5) or the striatum (anteroposterior, 0.0;
lateral, 3.0; ventral, 6.5) according the atlas of Paxinos and Watson (1982). Probes and screws were secured in place with dental
cement. Additional local anesthetic was then injected (under the skin)
around the wound area. After surgery, animals were placed in the same
container that they had been in before surgery and allowed to recover
for 24 hr before the microdialysis measurements, which were
performed in the same container.
Microdialysis procedure. Concentric microdialysis
probes with an exposed tip length of 3.0 mm were used. A flow rate of 2 µl/min was used during sample collection (probes were
perfused overnight at a rate of 0.5 µl/min. The
perfusion solution was a 2 mM phosphate buffer, pH 7.4, containing the following (in mM): 145 NaCl, 2.7 KCl, 1.2 CaCl2, 1.0 MgCl2, and 0.1 ascorbic acid. Probes
were calibrated in a solution containing 10 6
M aspartate, glutamate, glutamine, serine, and homoserine
or 107 M DA. The probes
exhibited a recovery of 14-18% (for all compounds). All probes were
perfused at 2 µl/min for 2-3 hr before local drug perfusion.
Chromatographic analysis of amino acids and dopamine.
For analysis of dopamine, samples were injected onto an HPLC with
electrochemical detection. This system employed a narrow-bore column
[2.1 mm inner diameter (i.d.), 3 µm C-18 particles, 10 cm long] and
a Bioanalytical Systems LC-4C potentiostat (West Lafayette, IN). The
Eapp was +0.55 V versus Ag/AgCl reference electrode.
The mobile phase consisted of: 9 gm/l
NaH2PO4, 575 mg/l octylsulfonic
acid, 8% acetonitrile (v/v), 250 mg/l
EDTA, and 250 µl/l triethylamine, pH 5.1. A detection limit of 5 fmol was routinely achieved.
The amount of glutamate and homoserine (internal standard) in the
perfusate was determined by precolumn derivatization with o-pthalaldehyde and mercaptoethanol, followed by HPLC with
fluorescence detection. This system used an Autosampler (Spectra System
AS 3000, Spectra-Physics, Fremont, CA), a gradient pump
(Spectra-Physics, model SP 8800), and a fluorescence detector
(Spectra-Physics, model SP 8410). The excitation and emission wave
lengths were set at 300 and 400 nM, respectively. A 3 µm,
C-18 (10 cm long, 4.2 mm i.d.) analytical column was used. The mobile
phase was a 0.1 M phosphate buffer containing 0.01 M EDTA, pH 6.4, and acetonitrile (with a gradient profile
of 13-22% acetonitrile over 12 min).
Data analysis. For statistical analysis, because of
the variability in resting basal levels, the glutamate data were
expressed as percentage of the mean of three basal values obtained
immediately before the treatment. Different groups (e.g., ketamine- or
saline-treated groups) were compared using Kruskal-Wallis ANOVA.
Significant differences (p < 0.05) from
saline-treated groups are depicted with asterisks on figures. The
dopamine data (absolute values in fmol/µl) were analyzed using
repeated measures ANOVA. In figures, levels are expressed as percentage
of the mean (±SEM) of the three basal values obtained immediately
before the treatment.
Histology. After the termination of each experiment, animals
were anesthetized with chloral hydrate and perfused intracardially with
saline, followed by 10% buffered formalin. Brains were removed and
stored in formalin. Serial sections of the fixed brains were cut at 100 µm intervals and stained with cresyl violet for probe placement
verification.
Materials. All reagents for the HPLC mobile phase and the
perfusion fluid were analytical grade and were obtained from Eastman Kodak (Rochester, NY) or J. T. Baker Chemical Company (Phillipsburg, NJ). LY293558 was a gift from Eli Lilly. Ketamine and
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were purchased from
Research Biochemicals (Natick, MA). A 10 mM CNQX stock
solution was prepared by dissolving CNQX in 0.1 M NaOH.
Before use, the stock solution was diluted to 50 µM with
the normal perfusion solution.
Spatial delayed alternation. Spatial delayed alternation
performance was tested using a T-maze as described previously (Verma and Moghaddam, 1996). The T-maze was constructed from Plexiglas and
painted a medium gray. The walls were 30 cm high, and the alleys were
15 cm wide. The length of the main alley was 50 cm, and the length of
the side alleys was 40 cm. The side alleys were closed off from the
main alley by movable doors. At the end of each side alley was a 2 cm
high barrier that concealed the food reward (one morsel of Froot Loops
cereal, General Mills, Kankakee, IL) from view. A third movable door
was mounted in the main alley. A holding cage was placed adjacent to
the T-maze for use during experiments with intertrial intervals. A
video camera was situated ~1 m above the T-maze to videotape the test
session. The T-maze was cleaned between different animals, but not
between different trials. Animals were handled for 3 d and then
allowed to explore the maze with all doors raised for 10 min for 2 d. After these 2 d, animals were food-restricted, each animal
receiving ~15 gm of food per day, and remained that way throughout
the experiment. After 2 d of food restriction, the adaptation
process continued for two more days by placing the animal in each side
arm with food behind the barrier, for 5 min. The animal was then placed in the other arm, which also contained food behind the barrier, for a 5 min stay. Next, the actual spatial alternation testing started. Each
rat received 10 trials per day. During the first trial of each day, a
Froot Loop morsel was presented in both goal arms. During the next 10 trials, the arm opposite to the one the animal had entered in the
previous trial was baited, except when the animal had gone to the empty
arm on the last trial. In that case, the food pellet was left in place
(hence, the baited side was changed only after the animal had
alternated). Once the animal entered either arm, the door was closed.
Ten seconds after entry to the arm, the animal was removed and returned
to the holding cage for a 10 sec intertrial interval. This training
continued until a criterion of 80% correct choices (of 10 trials) on
two consecutive days was achieved. Animals took 10-14 d to reach the criterion. Animals that did not reach the criterion by 20 d were rejected from the study. Approximately 5% of animals belonged to this
latter group.
RESULTS
Basal extracellular levels of glutamate or dopamine were
measured in 91 rats. The average extracellular dopamine values were 0.29 ± 0.05 fmol/µl (n = 41) in the PFC and
0.98 ± 0.1 fmol/µl (n = 7) in the striatum.
Average extracellular levels for glutamate were 0.8 ± 0.25 pmol/µl (n = 38) in the PFC and 0.64 ± 0.3 pmol/µl (n = 5) in the striatum. These values are not
corrected for in vitro recovery.
Effect of ketamine on extracellular glutamate levels in
the PFC
Figure 1 demonstrates the effect of
subanesthetic doses of ketamine on the extracellular levels of
glutamate in the PFC. All doses tested increased these levels
significantly (p < 0.05). The effect of 30 mg/kg ketamine remained significant (compared with the saline-treated
group) until 100 min after the injection, whereas the effect of 10 and
20 mg/kg ketamine subsided 60 and 80 min, respectively, after the
injection. The stress of saline injection produced an immediate
increase in glutamate efflux in some animals, similar to that observed
before (Moghaddam and Bolinao, 1994).
Fig. 1.
Effect of intraperitoneal injections of
subanesthetic doses of ketamine on the extracellular levels of
glutamate in the prefrontal cortex. All doses tested increased these
levels significantly compared with the saline injected groups.
Asterisks (*) denote significant differences from
saline-treated groups as determined by Kruskal-Wallis ANOVA
(n = 6 for 30 mg/kg; n = 7 for 20 mg/kg; n = 7 for 10 mg/kg groups).
[View Larger Version of this Image (35K GIF file)]
Injection of 50 mg/kg ketamine, which produced a short-lasting
sedation, did not increase the extracellular levels of glutamate significantly (Fig. 2). Furthermore, the anesthetic dose
of 200 mg/kg significantly decreased these levels. These levels
returned to baseline after the rebound from anesthesia, about 1 hr
after the injection. It should be noted that in some animals higher than baseline glutamate levels were observed after the cessation of
anesthesia; however, because of the variability of this response, there
was no significant increase.
Fig. 2.
Effect of intraperitoneal injections of anesthetic
doses of ketamine on the extracellular levels of glutamate in the
prefrontal cortex. Asterisks (*) denote significant differences as
compared with saline-treated group (n = 6 for 50 mg/kg;
n = 5 for 200 mg/kg).
[View Larger Version of this Image (28K GIF file)]
Effect of ketamine on cortical release of dopamine
In separate groups of animals, injection of a subanesthetic dose
(30 mg/kg, i.p.) of ketamine significantly increased the extracellular
levels of dopamine in this region (p < 0.001;
see Fig. 3). To determine whether the ketamine-induced
increase in the PFC is in part because of an increase in endogenous
glutamate and subsequent stimulation of non-NMDA receptors within the
PFC, the experiment above was repeated while the non-NMDA antagonist CNQX (50 µM) was locally perfused through the
microdialysis probe. Injection of ketamine in the CNQX-treated group
produced only a trend toward an increase (p = 0.07). Furthermore, the response of this group was significantly
(p < 0.05) less than those animals that
received ketamine in the absence of CNQX, suggesting that intra-PFC
application of CNQX reduced the stimulatory effect of ketamine on
dopamine release.
Fig. 3.
Effect of intraperitoneal injections of 30 mg/kg ketamine on the extracellular levels of dopamine in the
prefrontal cortex in the presence or absence of local infusion of CNQX.
Ketamine increased dopamine release significantly compared with
saline-injected groups as determined by two-way repeated- measures
ANOVA (p < 0.001, n = 9 for
ketamine-treated group; n = 5 for saline-treated group). Infusion of CNQX (50 µM) started 1 hr before
ketamine injection (n = 6). After this treatment,
injection of ketamine only produced a trend toward an increase
(p = 0.07). Furthermore, the effect of ketamine
in CNQX-treated animals was significantly lower than CNQX-untreated
animals (p < 0.05).
[View Larger Version of this Image (29K GIF file)]
Effect of ketamine in the striatum
To assess the regional specificity of subanesthetic doses of
ketamine, the effect of 30 mg/kg ketamine on the outflow of glutamate and dopamine in the striatum was examined (Fig. 4). The
effect of ketamine on extracellular levels of Glu was highly variable, and although a trend toward an increase was evident, it did not reach
significance. A significant (p < 0.01), but
small, increase of ~25% in dopamine release was observed in the
striatum.
Fig. 4.
Effect of intraperitoneal injections of 30 mg/kg
ketamine on the extracellular levels of dopamine (n = 7) and glutamate (n = 5) in the striatum. This
treatment caused a trend toward an increase in extracellular levels of
glutamate; however, because of high variability, there was no
statistically significant effect. The striatal extracellular levels of
dopamine did increase after the injection of 30 mg/kg ketamine
(p < 0.01); however, this increase was
significantly smaller than that observed in the prefrontal cortex
(demonstrated on Fig. 3, p < 0.005).
[View Larger Version of this Image (34K GIF file)]
Effect of systemic pretreatment with the AMPA/kainate receptor
antagonist, L Y293558, on ketamine-induced performance decrement of
spatial delayed alternation and dopamine release
As demonstrated on Figure 5, treatment with 30 mg/kg ketamine produces a deficit in spatial delayed alternation
performance, whereas systemic treatment with 0.1 and 1.0 mg/kg
LY293558, an AMPA/kainate receptor antagonist, did not affect the
performance of this task. However, pretreatment with LY293558
significantly attenuated the deficit produced by ketamine as compared
with saline pretreatment. Accordingly, pretreatment with LY293558
produced a significantly (p < 0.05) lower
increase of dopamine release in response to ketamine as compared with
saline pretreatment (Fig. 6).
Fig. 5.
Effect of ketamine (30 mg/kg) and LY293558 (0.1 and 1.0 mg/kg) on spatial delayed alternation performance in rats. Each
animal received 10 trials per day, and the mean ± SEM percentage
of correct responses per session is presented. The trials were
performed with a delay of 10 sec. The values in
parentheses represent the doses in mg/kg. Saline
(veh) and LY293558 (LY) were injected 15-20 min
before ketamine (ket) in groups designated as veh/ket and LY/ket, respectively. Pretreatment with LY293558 produced a significant reversal of ketamine-induced decrease in percentage of correct choice
in saline-treated rats (*p < 0.01, as compared with
the veh group, + p < 0.01 as compared with
the veh/ket group).
[View Larger Version of this Image (59K GIF file)]
Fig. 6.
Effect of intraperitoneal pretreatment with saline
or LY293558 (1.0 mg/kg) on ketamine (30 mg/kg)-induced increase in
dopamine release in the prefrontal cortex. Treatment groups paralleled the behavioral studies depicted on Figure 5. Injections were 20 min
apart. Significant increases in dopamine release were observed in both
LY293558+ketamine and saline+ketamine group (n = 7, p < 0.01; n = 8, p < 0.01, respectively). However, the increase after LY293558+ketamine
was significantly smaller than that observed after saline+ketamine
(p < 0.05, as determined by two-way
repeated-measures ANOVA).
[View Larger Version of this Image (26K GIF file)]
DISCUSSION
Effect of ketamine on glutamate efflux
The present study demonstrates that ketamine has a biphasic
influence on the outflow of Glu in the prefrontal cortex: low subanesthetic doses increase these levels, whereas an anesthetic dose
decreases these levels. Several mechanisms may account for the
stimulatory effect of low doses of ketamine on glutamate outflow. First, several lines of evidence suggest that NMDA receptors are located presynaptically and may be regulating the release of glutamate and other endogenous excitatory amino acids (Miwa et al., 1992; Smirnova et al., 1993; Huntley et al., 1994; Liu and Moghaddam, 1995;
Wang and Thukral, 1996). Second, ketamine, as well as other NMDA
antagonists, may produce disinhibition of GABAergic or other inhibitory
inputs to the glutamate-containing neurons, thereby enhancing the
firing rate of these glutamatergic neurons. Such disinhibition may
occur locally at the PFC and/or at regions with ascending glutamatergic
projections to the PFC.
The stimulatory effects of low doses of ketamine were dose-dependent to
the extent that the higher doses produced longer durations of response.
However, the magnitude of response did not vary among doses at early
time points. This may be expected in that during basal conditions the
excitatory effects mediated by glutamate at the NMDA receptor may be
partially blocked by the hyperpolarizing influence of tonically active
GABA neurons that impinge on PFC afferents and PFC pyramidal cells
(Houser et al., 1984; Smiley and Goldman-Rakic, 1993). Thus, low doses
of NMDA antagonists may be sufficient to reach maximum blockade of
these receptors. In that case, higher doses of ketamine will have
similar magnitudes, but longer duration of effect in light of the short
half-life of ketamine.
The inhibitory effect of an anesthetic dose of ketamine on
extracellular levels of glutamate agrees with previous reports indicating that anesthesia decreases the extracellular levels of
glutamate (Moghaddam and Bolinao, 1994). This decrease may be caused by
inhibition of other neuronal systems postsynaptic to NMDA
receptor-mediated neurotransmission. Nevertheless, the present finding
suggests that a decrease in the outflow of endogenous excitatory amino
acids may be common occurrence during anesthesia.
Ketamine (30 mg/kg) did not significantly increase Glu efflux in
the striatum. Although in some animals an increase in these levels was
evident, the high variability of response prevented this effect from
reaching statistical significance. We have frequently observed a higher
degree of variability in extracellular levels of Glu in the striatum as
compared with cortical regions (Moghaddam, 1993).
Mechanism by which ketamine increases dopamine release in the
prefrontal cortex
The stimulatory effect of ketamine on dopamine release in the PFC
was reduced by local application of the AMPA/kainate receptor antagonist CNQX at a concentration (50 µM) that by itself
does not affect basal release of dopamine in the PFC (Jedema and
Moghaddam, 1994). This finding suggests that ketamine may increase
dopamine release in the PFC by producing an initial increase in the
release of endogenous excitatory amino acid, such as glutamate, which in turn increases the release of dopamine by stimulating non-NMDA excitatory amino acid receptors. Indeed, our previous studies have
indicated that stimulation of AMPA or kainate receptors, but not the
NMDA receptors, readily increases dopamine release in the PFC (Jedema
and Moghaddam, 1996). Furthermore, similar reversal by CNQX was
observed previously when assessing the effect of stress, a treatment
that increases the outflow of glutamate (Moghaddam, 1993) and dopamine
(Abercrombie et al., 1989) in the PFC. Specifically, it was found that
pretreatment with CNQX significantly attenuated the stress-induced
increase of dopamine in this region (Jedema and Moghaddam, 1994),
suggesting that physiologically released glutamate (in response to
stress) activated dopaminergic neurotransmission in the PFC via
AMPA/kainate receptors.
Subanesthetic doses of ketamine increased dopamine release in the PFC
in a manner that was larger in magnitude and longer in duration than in
the striatum. Numerous other studies have indicated similar findings
with regard to regional specificity of PCP in activating dopamine
neurotransmission (Rao et al., 1989; Hondo et al., 1994; Hertel et al.,
1996; Nishijima et al., 1996). One reason for the regional specificity
of ketamine and PCP may be that, as suggested by the nonsignificant
effect of ketamine in the striatum, the NMDA receptor antagonists are
more effective in releasing glutamate in the PFC relative to the
striatum. Another may be differences in the manner in which glutamate,
released by these antagonists, may stimulate the release of dopamine in the PFC versus the striatum. Previous studies investigating this interaction indicate that stimulation of kainate or AMPA receptors is
much more potent in increasing dopamine release in the PFC as compared
with the striatum (Westerink et al., 1992; Jedema and Moghaddam,
1996).
Systemic AMPA/kainate receptor antagonists attenuate the influence
of ketamine on dopamine release and spatial delayed alternation
performance
Behavioral tests that impose a delay between a cue and execution
of a motor response are thought to assess "working memory," a
cognitive function that is dependent on the functional integrity of the
prefrontal cortex (Goldman-Rakic, 1987). In the rat, T-maze-delayed alternation (Simon et al., 1980; Brito et al., 1982; Stam et al., 1989;
De Brabander et al., 1991) as well as operant
delayed-matching-to-position (Dunnett, 1985; Broersen et al., 1994),
are routinely used to assess this function. Previous studies from our
laboratory have reported that subanesthetic doses of ketamine impair
the performance of rats in a T-maze-delayed alternation paradigm (Verma
and Moghaddam, 1996). Furthermore, it was demonstrated that this
impairment is reversed by pretreatment with raclopride and haloperidol,
which have in common their antagonistic properties at dopamine D2
receptors, suggesting that activation of dopamine neurotransmission at
the D2 receptor contributes to the behavioral impairment of ketamine. This observation is in line with the work of Arnsten and coworkers that
activation of dopamine neurotransmission in the PFC impairs performance
of delayed alternation tasks (Arnsten et al., 1994; Murphy et al.,
1996).
The neurochemical studies presented here that demonstrate that
activation of dopamine neurotransmission by ketamine may be secondary
to activation of AMPA/kainate receptors would predict that the
behavioral decrement produced by ketamine should be ameliorated by
AMPA/kainate antagonists. This hypothesis was tested by examining the
effect of pretreatment with an AMPA/kainate receptor antagonist on the
ketamine-induced T-maze-delayed alternation performance decrement.
LY293558 (Schoepp et al., 1995) was chosen because, unlike CNQX, it
readily crosses the blood brain barrier. The doses of LY293558 used in
the present study (0.1 and 1.0 mg/kg) were much lower than the doses
( 10 mg/kg) that produce motor retardation and sedation (Schoepp et
al., 1995). It was found that LY293558 by itself did not affect delayed
alternation performance, in agreement with previous studies
demonstrating that other AMPA/kainate receptor antagonists do not
affect learning and memory in the rodent (Parada et al., 1992).
However, LY293558 ameliorated the performance decrement elicited by
ketamine, suggesting that activation of AMPA/kainate receptors may
contribute to the NMDA receptor antagonist-induced performance
decrement. In agreement with these behavioral findings, parallel
microdialysis studies demonstrated that pretreatment with LY293558
reduces the ketamine-induced increase of dopamine release in the PFC.
It is important to note that pretreatment with LY293558 only partially
reversed the behavioral and dopaminergic effects of ketamine. This may
be because of the relatively small doses of LY293558 used in the
present study. Furthermore, other mechanisms that are independent of
AMPA/kainate receptor activation are likely to contribute to the
behavioral effects of ketamine. Nonetheless, the findings above suggest
that enhancement of glutamatergic neurotransmission at AMPA/kainate
receptors contributes, at least in part, to cognitive impairments and
cortical dopaminergic activation elicited by ketamine.
CONCLUSIONS
The behavioral syndrome produced by ketamine (and PCP) in humans
and laboratory animals has been primarily attributed to postsynaptic reduction of glutamatergic neurotransmission at the NMDA
receptor. The present findings demonstrate that ketamine and PCP may
exert at least part of their effect in the PFC by activation
of glutamatergic neurotransmission at AMPA/kainate receptors. This is
supported by findings that subanesthetic doses of ketamine increase Glu efflux and that AMPA/kainate receptor antagonists attenuate
ketamine-induced PFC dopamine release and cognitive impairment. It is
noteworthy that antagonists of AMPA/kainate receptors reverse NMDA
receptor antagonist-induced neurodegeneration (Olney and Farber, 1995; Sharp et al., 1995), hyperlocomotion (Hauber and Andersen 1993; Willins
et al., 1993; Bubser et al., 1995), and stereotypy (our unpublished
observations). An important implication from these findings, therefore,
may be that hyperactivation of non-NMDA receptors, as opposed to a
"glutamatergic deficiency," may account for some of the cognitive
deficits and schizophrenia-like symptoms of NMDA receptor antagonists.
Hence, low doses of non-NMDA glutamate antagonists may be effective for
treatment of cognitive disorders in which NMDA receptor hypofunction is
suspect. Importantly, AMPA/kainate receptor antagonists also reduce the
psychostimulant-induced activation of dopaminergic neurotransmission in
limbic regions (Pap and Bradberry, 1995) and thus may be effective
antipsychotics not only by reversing the NMDA receptor-induced
deficiencies, but also by reducing the putative limbic
hyperdopaminergic state in schizophrenia.
FOOTNOTES
Received Sept. 23, 1996; revised Nov. 21, 1996; accepted Nov. 22, 1996.
This work was supported in part by PHS Award MH48404 (B.M.), the
Scottish Rite Foundation (B.M.), the Veterans Administration Merit
Award (J.K.), and Centers for Schizophrenia and PTSD. We thank Drs.
John Krystal and Steve Bunney for helpful discussions and Malu Bolinao
for technical assistance.
Correspondence should be addressed to Dr. Bita Moghaddam, Department of
Psychiatry, Yale University School of Medicine, VA Medical Center
116A12, West Haven, CT 06516.
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Compound via MeSH
