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 Previous Article
The Journal of Neuroscience, July 15, 1998, 18(14):5545-5554
Corticolimbic Dopamine Neurotransmission Is Temporally
Dissociated from the Cognitive and Locomotor Effects of
Phencyclidine
Barbara
Adams and
Bita
Moghaddam
Department of Psychiatry, Yale University School of Medicine,
Veterans Administration Medical Center, West Haven, Connecticut
06516
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ABSTRACT |
The behavioral syndrome produced by phencyclidine (PCP) and its
analog ketamine represents a pharmacological model for some aspects of
schizophrenia. Despite the multifaceted properties of these drugs, the
main mechanism for their psychotomimetic and cognitive-impairing
effects has been thought heretofore to involve the corticolimbic
dopamine system. The present study examined the temporal relationship
between alterations in corticolimbic dopamine and glutamate
neurotransmission and two dopamine-dependent behavioral effects of PCP
in the rodent that have relevance to the clinical phenomenology,
namely, impairment of working memory, which is used to model the
frontal lobe deficits associated with schizophrenia, and
hyperlocomotion, which is used as a predictor of the propensity of a
drug to elicit or exacerbate psychosis. PCP increased dopamine and
glutamate efflux in the prefrontal cortex and nucleus accumbens, as
measured by microdialysis. The increase in dopamine in both regions
remained elevated well above baseline 2.5 hr after the injection, at
which time the experiment was terminated. However, locomotor activity
returned to baseline in <2 hr after injection. Furthermore, impaired
performance in a discrete trial delayed alternation task, a rodent
working memory task, was only evident up to 60 min after PCP injection;
animals tested 80 min after injection, when cortical dopamine release was elevated at 300% of baseline, did not exhibit impaired
performance. These findings indicate that activation of dopamine
neurotransmission is not sufficient to sustain PCP-induced locomotion
and impairment of working memory. Thus, effects of PCP, including a
glutamatergic hyperstimulation, may be necessary to account for the
psychotomimetic and cognitive-impairing effects of this drug.
Key words:
prefrontal cortex; nucleus accumbens; microdialysis; PCP; schizophrenia; working memory; glutamate; NMDA; ketamine; drug
abuse
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INTRODUCTION |
Clinical studies and case reports
over the last 3 decades have consistently reported that a single
exposure to phencyclidine (PCP) or ketamine produces behavioral
disruptions in healthy individuals that mimic some aspects of the
deficit and positive symptoms associated with schizophrenia (Luby et
al., 1959 ; Davies and Beech, 1960; Bakker and Amini, 1961; Krystal et
al., 1994; Malhotra et al., 1996). Therefore, these drugs are used
routinely as clinical and animal models of this disorder, with the
underlying assumption that neuronal mechanisms responsible for some
PCP-induced disruptions of normal brain function may be relevant to the
pathophysiology of schizophrenia.
Consistent with clinical studies, subanesthetic doses of ketamine and
PCP, as well as other NMDA receptor antagonists, produce cognitive
disruptions as measured by a battery of memory and learning-related cognitive tasks in the rodent (Handelmann et al., 1987; Wesierska et
al., 1990; Hauber and Andersen, 1993; Verma and Moghaddam, 1996;
Jentsch et al., 1997a) and primate (Byrd et al., 1987; Hudzik and
Wenger, 1993; Javitt et al., 1996; Jentsch et al., 1997b). In addition,
they produce stereotypy and impair social behavior in both species
(Schlemmer et al., 1978; Sturgeon et al., 1979; Steinpreis et al.,
1994; Sams-Dodd, 1996) and at moderate doses increase locomotor
activity in the rodent (Sturgeon et al., 1979; Greenburg and Segal,
1985).
Despite the well established involvement of nondopaminergic mechanisms
in the reinforcing and disruptive effects of PCP and ketamine (Keith et
al., 1991; Bakshi et al., 1994; Kitaichi et al., 1994; Ogawa et al.,
1994; Carlezon and Wise, 1996; Hutson and Hogg, 1996; Gleason and
Shannon, 1997), a major mechanism responsible for the psychotomimetic
effects of these drugs is thought to involve dopaminergic
neurotransmission (Kornhuber et al., 1990; Javitt and Zukin 1991;
Carlsson et al., 1993; Iversen, 1995; Steinpreis, 1996; Breier et al.,
1998; Smith et al., 1998). This is based on two lines of evidence.
First, PCP increases dopamine release and turnover in the prefrontal
cortex and limbic striatal regions (Doherty et al., 1980; Deutch et
al., 1987; Carboni et al., 1989; Steinpreis and Salamone, 1993; Hondo
et al., 1994; Hertel et al., 1996; Verma and Moghaddam, 1996), thus
producing a limbic hyperdopaminergic state. This mechanism supports the well established "dopamine hypothesis of schizophrenia" and is consistent with recent imaging studies describing dopamine
hyperactivity in schizophrenics (Laruelle et al., 1996; Breier et al.,
1997). Of note, although chronic treatment with this class of drugs
reduces dopamine metabolite levels in cortical tissue (Jentsch et al., 1997a,b), it produces a sustained increase in resting extracellular levels of dopamine in the prefrontal cortex (Lindefors et al., 1997),
suggesting that the cortical hyperdopaminergic effect persists after
chronic treatment. Second, dopamine antagonists and/or lesions of
dopamine pathways reduce the effects of PCP on two behavioral measures
that are thought to have relevance to clinical symptomatology: cognitive tasks involving working memory, which are used routinely to
model some aspects of frontal lobe deficits associated with schizophrenia, and locomotor activity, which is used in preclinical studies as a predictor of the propensity of a drug to induce or exacerbate psychosis in man (Castellani and Adams, 1981; Greenburg and
Segal, 1985; French, 1986; Carlsson et al., 1993; Jackson et al., 1994;
Ogren and Goldstein, 1994; Steinpreis et al., 1994; Krystal et al.,
1995; Goldman-Rakic, 1996; Verma and Moghaddam, 1996). Based primarily
on the these findings, the major emphasis of most preclinical and
clinical studies that use PCP or ketamine as putative models of
schizophrenia, in particular those studies that assess the
etiology or treatment options for the cognitive deficits associated
with schizophrenia, is the dopamine system (Johnson and Jones, 1990;
Krystal et al., 1995; Verma and Moghaddam, 1996; Jentsch et al.,
1997a,b; Breier et al., 1998; Smith et al., 1998).
However, impairment of working memory-related tasks by ketamine or PCP
is only partially ameliorated with dopamine D2 receptor antagonists and
is not affected by other dopamine antagonists (Krystal et al., 1995;
Verma and Moghaddam, 1996), and locomotor effects of PCP are blocked
only at high cataleptic doses of dopamine antagonists (Castellani and
Adams, 1981; Ogren and Goldstein, 1994). In fact, evidence for a
temporal relationship between activation of corticolimbic dopamine
release and the cognitive and locomotor effects of PCP is lacking. The
present study was undertaken to establish whether such a relationship
exits.
Recent studies have demonstrated that ketamine and other NMDA receptor
antagonists also increase extracellular levels of glutamate (Liu and
Moghaddam, 1995; Moghaddam et al., 1997). Although there is controversy
on the significance of extracellular glutamate measures (Timmerman and
Westerink, 1997), other lines of evidence suggest that increases in the
synaptic availability of glutamate and postsynaptic activation of
glutamate receptors may produce cognitive, locomotive, neurotoxic, and
dopaminergic effects of NMDA receptor antagonists (Hauber and Andersen,
1993; Willins et al., 1993; Bubser et al., 1995; Olney and Farber,
1995; Sharp et al., 1995; Moghaddam et al., 1997). Thus, we also
performed concomitant measures of extracellular glutamate and compared
this response in the prefrontal cortex and nucleus accumbens to
dopaminergic and behavioral effects of PCP.
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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. Male Sprague Dawley rats (275-325 gm) were used
throughout the study. Microdialysis probes were implanted while the
rats were under halothane anesthesia. Animals were placed in a
stereotaxic frame with blunt ear bars, and a small incision (5-7 mm)
was made in the skin over the skull. The wound margin was infiltrated
with lidocaine. Holes were drilled for two skull screws and two
concentric microdialysis probes positioned bilaterally in the
prefrontal cortex [anterioposterior (AP), 3.2; lateral (L), 1.8 set at
a 10° angle; ventral (V),  6.5] and in the nucleus accumbens shell (AP, 1.8; L, 1.0; V, 8.4) with respect to bregma (Paxinos and Watson,
1982). Probes and skull screws were secured in place with dental
cement. After surgery, animals were placed in a clear polycarbonate cage (44 × 22 × 21 cm) with food, water, and bedding.
Animals were allowed to recover for 24 hr before microdialysis samples were taken. Probes were perfused with perfusion solution (see below) at
0.5 µl/min overnight and 2.0 µl/min during the experiment.
Microdialysis procedure. Concentric microdialysis probes
with an exposed tip length of 3.0 mm for prefrontal cortex and 2.0 mm
for nucleus accumbens were used. The perfusion solution contained (in
mM): 145 NaCl, 2.7 KCl, 1.0 MgCl2, and
1.2 CaCl2. A flow rate of 2 µl/min was used during the
sample collection. Samples were collected at 20 min intervals. After
collection, 5 µl of the sample was removed and added to disposable
autosampler vials containing homoserine (an internal standard) and was
later analyzed for glutamate (see below). The rest of the sample was
immediately injected onto an HPLC with electrochemical detection for
analysis of dopamine.
Chromatographic analysis of amino acids and dopamine. The
amount of dopamine in the dialysis samples was measured by HPLC with
electrochemical detection. This system used a 10 cm narrow-bore column
[2.0 mm inner diameter (i.d.); 3 µm C-18 particles] (Keystone, Bellefonte, PA) and a Bioanalytical Systems LC-4C potentiostat (BAS,
West Lafayette, IN). The Eapp was +0.55 V versus
Ag/AgCl reference electrode. The mobile phase consisted of 9 gm/l
NaH2PO4, 640 mg/l octylsulfonic acid,
7.2% acetonitrile (v/v), 250 mg/l EDTA, and 350 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 0-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 (SP 8800; Spectra-Physics), and a fluorescence detector (SP 8410;
Spectra-Physics). The excitation and emission wavelengths were set at
300 and 400 nM, respectively. A 10 cm, C-18, 4.2 mm i.d.
analytical column (Keystone, Bellefonte, PA) was used. The mobile phase
was 0.1 M phosphate buffer, pH 6.4, containing 0.01 M EDTA and acetonitrile with a gradient profile of 12-22%
over 12 min.
Locomotor activity and stereotypy rating. A data acquisition
system (Med Associates, St. Albans, VT) was used to record the activity
during the microdialysis experiments. Four pairs of photocells were
spaced evenly along the length of the cage. Nonconsecutive beam breaks
were totaled every 20 min, which was coordinated with the collection
time of the microdialysis samples. Stereotypy was rated by a trained
observer according to method of Kelley and Delfs (1994).
Discrete trial delayed alternation paradigm. Spatial delayed
alternation performance was tested using a discrete trial T-maze delayed alternation paradigm (in part, adapted from Freeman and Stanton, 1992). Animals were handled and trained in a gray Plexiglas T-maze, as described previously (Verma and Moghaddam, 1996). However, instead of 10 trials of continuous alternation, which necessitates imposing long delay periods in between trials as rats become
overtrained, animals were presented first with a forced run, i.e., they
were given access to only one arm of the maze and rewarded (half of a
morsel of Froot Loops cereal; General Mills, Kankakee, IL) after entering that arm. After a 10 sec delay, they were presented with both
arms and were rewarded for entering the arm that they had not entered
on the previous (forced) run. Animals were given 10 randomly chosen
forced runs, followed by 10 choice runs. Animals were trained until a
criterion of 80% correct choices on 2 consecutive days was
achieved.
Histology. After the termination of each experiment, animals
were anesthetized with chloralhydrate 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. Probe placement was
verified for all of the data sets used in this study.
Materials. All reagents for the HPLC mobile phase and the
perfusion fluid were analytical grade and were obtained from Eastman Kodak (Rochester, NY), J. T. Baker Chemical Company (Phillipsburg, NJ), or Sigma (St. Louis, MO). PCP was purchased from Sigma.
Data analysis. For microdialysis and locomotor data, two-way
ANOVA with time as the repeated measures was used to compare the
drug-treated and control groups. Within each group, analyses were
conducted by one-way repeated measures ANOVA. Significant main effects
were analyzed further by Tukey post hoc comparison of means.
For microdialysis studies, both absolute values (femtomoles per
microliter not corrected for recovery) and percentage of the mean ± SEM of the three basal values obtained immediately before the
treatment were analyzed. For the activity data, the nonconsecutive beam
breaks in 20 min (to correspond with microdialysis sample collection)
was used for analysis. The delayed alternation data were compared by
multifactorial ANOVA followed by Tukey post hoc analysis.
Significance was set at p  0.05.
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RESULTS |
Effects of PCP on dopamine and glutamate efflux in the
prefrontal cortex
All microdialysis data are shown in terms of both absolute levels
of dopamine and glutamate measured in the dialysate and percent
increase from baseline. The latter is to facilitate the comparison of
response between different regions and compounds measured.
Intraperitoneal injection of 5 mg/kg PCP produced a robust
sixfold increase in extracellular levels of dopamine in the prefrontal cortex (Fig. 1). This increase in
dopamine peaked at 40 min after injection and declined afterward.
However, dopamine levels remained elevated significantly above baseline
140 min after the injection, at which time the experiment was
terminated.
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Figure 1.
Effect of PCP (5 mg/kg, i.p.) on the extracellular
levels of dopamine in the prefrontal cortex. The top
illustrates the data in terms of percentage of baseline (mean ± SEM of the three basal values obtained immediately before the
injection), and the bottom indicates the absolute
dopamine concentration in the dialysis samples not corrected for probe
recovery. Two-way ANOVA with time as the repeated measures indicated a
significant group × time effect (p < 0.001) between the PCP (n = 7) and saline
(n = 6) groups. Asterisks indicate
significant differences from the saline-treated group corresponding to
the same postinjection time.
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PCP also produced a significant increase in extracellular glutamate
levels in the prefrontal cortex (Fig. 2).
This increase was apparent immediately and continued to rise for the
first hour after injection. Glutamate levels remained elevated at
maximal levels when the experiment was terminated 140 min after the PCP injections. The glutamate response was more variable than that observed
with dopamine, which is consistent with our previous observations that
dialysate glutamate levels during baseline or after pharmacological
challenges (or stress) are more variable than dopamine levels.
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Figure 2.
Effect of PCP (5 mg/kg, i.p.) on the extracellular
levels of glutamate in the prefrontal cortex. The top
illustrates the data in terms of percentage of the mean ± SEM of
the three basal values obtained immediately before the injection, and
the bottom is the absolute dopamine concentration in the
dialysis samples not corrected for probe recovery. Two-way ANOVA with
time as the repeated measures indicated a significant group × time effect (p < 0.04) between the PCP
(n = 7) and saline (n = 6)
groups. Asterisks indicate significant differences from
the saline-treated group corresponding to the same postinjection
time.
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Effect of PCP on discrete trial delayed
alternation performance
To examine the time-dependent effect of PCP on a working memory
task that is dependent on the functional integrity of the dopamine
projections to the prefrontal cortex, rats were trained in a delayed
alternation paradigm (Simon, 1981; Bubser and Schmidt, 1990). PCP and
other NMDA antagonists produce disruption of delayed-response tasks
presumably by activating dopamine neurotransmission in the prefrontal
cortex (Verma and Moghaddam, 1996; Zahrt et al., 1997). Animals were
trained to perform at 80% correct choice (20% error) at a delay of 10 sec on at least 2 consecutive days. They were then injected with
vehicle or PCP (Fig. 3). Saline-injected
animals were tested 20 or 40 min after injection. PCP-injected animals were tested at 20, 40, 60, or 80 min after injection (i.e., each rat
was tested only once after PCP at one of these times after injection).
Because of the profound stereotypy and hyperlocomotion apparent in some
rats 20 min after receiving PCP (see below), only two rats were
properly tested at 20 min after injection, both of which performed at
50% correct. Animals tested 40 and 60 min after PCP injection showed
impairment in performance of this task. In contrast, an impairment was
not observed in rats tested 80 min after injection.
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Figure 3.
Time-dependent effect of intraperitoneal injection
of PCP on discrete trial delayed alternation performance. Only two rats
were properly tested at 20 min after injection, both of which performed
at 50% correct. (Three other rats tested at this time ran up and down
the main alley of the maze and did not enter the side arms or remained
in the start box exhibiting profound head rolling.) Animals tested 40 and 60 min after PCP injection showed significant impairment compared
with the saline-treated group (p < 0.05).
Rats tested 80 min after PCP injection did not display an
impairment.
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Figure 4 displays the PCP-induced
relative increase in dopamine and glutamate levels in the prefrontal
cortex, along with the percent of error exhibited during the
delayed-alternation task corresponding to the same time after PCP
injection. As shown, 20-60 min after injection an increase in percent
of error is accompanied by an increase in glutamate and dopamine
efflux. However, 80 min after injection when the delayed alternation
performance is no longer impaired, dopamine and glutamate levels in the
prefrontal cortex, as well as dopamine levels in the nucleus accumbens
(see below), remain elevated well above baseline.
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Figure 4.
Temporal comparison of the increase in
extracellular levels of dopamine and glutamate (displayed as percent of
preinjection value) and performance in delayed alternation paradigm
corresponding to the time that the neurochemical analysis was performed
after PCP injection.
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Effect of PCP on dopamine and glutamate efflux in the
nucleus accumbens
Intraperitoneal injection of 5 mg/kg PCP produced a significant
increase of nearly 300% in extracellular levels of dopamine in the
nucleus accumbens (Fig. 5). Similar to
the effect seen in the prefrontal cortex, the increase in dopamine
peaked at 40 min after injection and remained significantly elevated
above baseline for the duration of the experiment. The relative
magnitude of this increase compared with baseline was significantly
smaller (p < 0.01) than that observed in the
prefrontal cortex.
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Figure 5.
Effect of PCP (5 mg/kg, i.p.) on the extracellular
levels of dopamine in the nucleus accumbens. The top
illustrates the data in terms of percentage of the mean ± SEM of
the three basal values obtained immediately before the injection, and
the bottom is the absolute dopamine concentration in the
dialysis samples not corrected for probe recovery. Two-way ANOVA with
time as the repeated measures indicated a significant group × time effect (p < 0.01) between the PCP
(n = 8) and saline (n = 8)
groups. Asterisks indicate significant differences from
the saline-treated group corresponding to the same postinjection
time.
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PCP also produced a significant increase in extracellular glutamate
levels in the nucleus accumbens compared with baseline (Fig.
6). This increase peaked immediately and
declined toward baseline 40 min after injection. Whereas glutamate
levels remained elevated above baseline (i.e., preinjection value),
because of the variability in both saline- and PCP-treated data groups,
the response to PCP was significantly different from saline-injected rats only for the first two samples collected after PCP injection.
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Figure 6.
Effect of PCP (5 mg/kg, i.p.;
n = 6) or saline (n = 6) on the
extracellular levels of glutamate in the nucleus accumbens. The
top illustrates the data in terms of percentage of the
mean ± SEM of the three basal values obtained immediately before
the injection, and the bottom is the absolute dopamine
concentration in the dialysis samples not corrected for probe recovery.
PCP produced a significant increase in glutamate levels relative to
preinjection values (p < 0.05, using ANOVA
with time as the repeated measures). Asterisks indicate
significant differences from preinjection values.
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Effect of PCP on locomotor activity and stereotypy
PCP elicited an immediate and profound hyperlocomotion and
stereotypy (Fig. 7). The locomotor count
peaked in the first 20 min after injection and declined to baseline
levels 100 min after injection. The repetitive behaviors exhibited
after receiving PCP included head rolling, circling, peddling, hand
rubbing, sniffing, and mouth movements. The time course of the
stereotypy followed that of the locomotor response. The highest
stereotypy score occurred during the first 20 min after injection. The
head-rolling response subsided in most animals 40-60 min after
injection. All other repetitive behaviors subsided 100-120 min after
injection.
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Figure 7.
Effect of PCP and saline injection on locomotor
activity (top) and stereotypy score
(bottom). Two-way ANOVA with time as the repeated
measures indicated a significant group × time effect
(p < 0.001) between the PCP
(n = 8) and saline (n = 8)
groups. Asterisks indicate significant differences from
the saline-treated group corresponding to the same postinjection
time.
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Dopamine projections to the nucleus accumbens have been strongly
associated with PCP-induced locomotion because intra-accumbens application of PCP elicits locomotion (McCullough and Salamone, 1992),
and lesions of the dopaminergic projections to the nucleus accumbens
block the locomotor stimulating effects of PCP (French, 1986;
Steinpreis and Salamone, 1993; Ouagazzal et al., 1994). Therefore, in
the present study the magnitude and duration of the effects of PCP on
locomotor activity and dopamine release in the nucleus accumbens were
compared. Figure 8 demonstrates correlational analysis and the temporal comparison of the locomotion and extracellular dopamine data. Although a significant correlation between these two measures was obtained (Fig. 8, top), there
was a dissociation in the time course of the response in that despite a
sustained elevation in extracellular levels of dopamine, nearly double
the resting levels, the locomotor activity declined toward preinjection
resting levels. A similar analysis performed with locomotor activity
and extracellular levels of glutamate in response to PCP is
demonstrated in Figure 9. Similar to that
observed with dopamine, a significant correlation was apparent between
these two measures; however, despite elevated extracellular glutamate levels 2 hr after PCP injection (relative to preinjection values), the
increase in locomotion subsided.
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Figure 8.
Correlational analysis for concomitant 20 min
measurements (top) and the temporal relationship
(bottom) between the locomotor activity and
extracellular levels of dopamine in the nucleus accumbens after
PCP.
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Figure 9.
Correlational analysis for concomitant 20 min
measurements (top) and the temporal relationship
(bottom) between the locomotor activity and
extracellular levels of glutamate in the nucleus accumbens after
PCP.
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DISCUSSION |
Subanesthetic doses of PCP and its analog ketamine increase
dopamine release in rodents (Hondo et al., 1994; Verma and Moghaddam, 1996) and humans (Breier et al., 1998; Smith et al., 1998), and dopamine antagonists ameliorate the behavioral disruption caused by
these drugs, which may have relevance to schizophrenic symptomatology (Freed et al., 1980; Ogren and Goldstein, 1994; Krystal et al., 1995;
Verma and Moghaddam, 1996). Hence, dopamine hyperfunction has been
associated with the psychotomimetic properties of these drugs. The
present study examined whether activation of dopamine release in the
prefrontal cortex and nucleus accumbens is temporally related to those
behavioral effects of PCP that have relevance to the clinical
phenomenology: impairment of working memory, which is used to model the
frontal lobe deficits associated with schizophrenia, and
hyperlocomotion, which is used as a predictor of the propensity of a
drug to elicit or exacerbate psychosis. In light of recent findings
that the dopamine-releasing effects of the NMDA receptor antagonists
may be in part attributable to activation of glutamatergic neurotransmission (Moghaddam et al., 1997), the time course of dopaminergic and behavioral effects of PCP was also compared with glutamate efflux.
PCP-mediated neurochemical effects in the prefrontal cortex and
nucleus accumbens
In agreement with previous studies, PCP increased dopamine release
in the prefrontal cortex and nucleus accumbens (Carboni et al., 1989;
Bristow et al., 1993; Steinpreis and Salamone, 1993; Hondo et al.,
1994; Hertel et al., 1996; Nishijima et al., 1996). This increase was
larger in magnitude in the prefrontal cortex than in the nucleus
accumbens, but the duration of effect was similar in both regions.
This is the first report of PCP increasing glutamate efflux in the
prefrontal cortex. This observation is consistent with the effect of
ketamine and other NMDA receptor antagonists, which increases glutamate
efflux in a dose-dependent and TTX-sensitive manner (Liu and Moghaddam,
1995; Moghaddam et al., 1997). Glutamate levels in the nucleus
accumbens also increased in response to PCP. This effect was more
variable and shorter in duration than the effect seen in the prefrontal
cortex.
Although PCP, at least at high anesthetic doses, has an affinity for
the dopamine transporter (Javitt and Zukin, 1991), the increase in
extracellular levels of cortical dopamine observed at the moderate dose
of 5 mg/kg is unlikely to be attributable to blockade of dopamine
uptake. The axonal distribution of the dopamine transporter protein in
the rodent medial prefrontal cortex is highly restricted compared with
striatal regions (Sesack et al., 1998). Consistent with this pattern of
distribution, dopamine uptake blockers, such as cocaine, are relatively
ineffective in increasing extracellular levels of dopamine in the
prefrontal cortex (Moghaddam and Bunney, 1989), although they
profoundly increase these levels in the nucleus accumbens and the
striatum (Hurd and Ungerstedt, 1989). In contrast, the pattern of
increase in dopamine release after 5 mg/kg PCP is opposite to the
axonal density of the dopamine transporter; extracellular dopamine
levels increase to nearly 600% above baseline in the prefrontal
cortex, 300% above baseline in the nucleus accumbens, and 50% above
baseline in the striatum (Nishijima et al., 1996; our unpublished
observations). Thus, it is unlikely that blockade of dopamine uptake
contributes significantly to the increase in extracellular dopamine
levels produced by moderate doses of PCP.
In anesthetized preparations, systemic administration of PCP and other
NMDA antagonists increase the firing rate of dopamine neurons (French,
1994), suggesting that these drugs enhance impulse-dependent dopamine
release. However, in awake rats, application of NMDA receptor
antagonists to dopamine cell body regions reduces dopamine release in
the nucleus accumbens (Karreman et al., 1996; Westerink et al., 1996)
and prefrontal cortex (Takahata and Moghaddam, 1998), indicating that
the increase in dopamine release after systemic NMDA antagonists (in
the absence of anesthesia) is mediated by mechanisms that regulate
presynaptic release of dopamine. This is consistent with reports that
local application of PCP in the prefrontal cortex dose-dependently
increases dopamine release in this region (Hondo et al., 1994). One
mechanism that may mediate this local effect and account for the
preferential stimulatory effect of PCP (and other NMDA receptor
antagonists, including MK801; Wedzony et al., 1994) on cortical
dopamine release may involve a hyperglutamatergic state at non-NMDA
receptors. The present study and previous reports (Liu and Moghaddam,
1995; Moghaddam et al., 1997) indicate that PCP and other NMDA receptor
antagonists increase extracellular levels of glutamate. The mechanism
for and the functional significance of this increase is not well
established. However, reports that AMPA and kainate receptor
antagonists reduce the increase in locomotion (Hauber and Andersen,
1993; Willins et al., 1993; Bubser et al., 1995), cognitive deficits
(Moghaddam et al., 1997), neurodegeneration (Olney and Farber, 1995;
Sharp et al., 1995), and cortical dopamine release (Moghaddam et al., 1997) associated with ketamine, MK801, or PCP suggest that an increase
in the synaptic availability of glutamate and subsequent activation of
non-NMDA glutamate receptors may be associated with these drugs.
Interestingly, dopamine projections to the prefrontal cortex are more
sensitive to AMPA and kainate receptor regulation, both at the cell
body (Takahata and Moghaddam, 1998) and the terminal level (Jedema and
Moghaddam, 1996) than projections to the ventral striatum, suggesting
that glutamate hyperfunction at non-NMDA receptors may preferentially
increase dopamine release in the prefrontal cortex compared with
subcortical regions.
The pattern of response in extracellular glutamate levels in the
prefrontal cortex after PCP had a different profile than that observed
for dopamine; whereas dopamine levels peaked at 40 min and declined
afterward, glutamate levels continued to rise above baseline during the
first hour after injection and remained maximally elevated for the
remainder of the experiment. The different temporal response pattern
between the increase in extracellular glutamate and dopamine, in
particular, a decline in dopamine levels while the glutamate levels
were sustained at maximal levels, questions the idea that activation of
glutamate release (and subsequent stimulation of AMPA and kainate
receptors) may be a contributing factor to dopaminergic activation.
However, both AMPA and kainate receptors desensitize rapidly in
response to repeated stimulation (Kiskin et al., 1986; Otis et al.,
1996; Jones et al., 1997; Wilding and Huettner, 1997). Hence, despite a
sustained increase in glutamate levels after PCP, a decline in dopamine
release may be expected if activation of AMPA or kainate receptors
plays a part in stimulating this release.
Comparison of PCP-mediated cognitive and neurochemical effects
PCP impaired performance of a discrete trial delayed alternation
task, a rodent working memory task that is dependent on the functional
integrity of the prefrontal cortex (J. M. Aultman and B. Moghaddam,
unpublished observations). This finding is consistent with other
reports that acute administration of noncompetitive NMDA antagonists
produces deficits in frontal lobe-dependent tasks in rodents and humans
(Hauber and Andersen, 1993; Krystal et al., 1994; Verma and Moghaddam,
1996). This impairment was apparent when animals were tested at 20, 40, or 60 min after PCP injection. However, animals that were tested 80 min
after the injection, at which time both dopamine and glutamate levels
in the prefrontal cortex (and the nucleus accumbens) were elevated over
200% of basal values, did not display an impairment. These findings
suggest that activation of dopamine neurotransmission is not sufficient to produce the working memory deficit associated with PCP.
The dissociation between maze performance and activated dopamine
release was unexpected, because working memory impairment produced by
ketamine is ameliorated by pretreatment with dopamine D2 receptor
antagonists (Krystal et al., 1995; Verma and Moghaddam, 1996) and
evidence for rapid desensitization of postsynaptic D2 receptors is
generally lacking (Filtz et al., 1993; White, 1996; Ng et al., 1997).
Based on the present findings, it may be postulated that reduction of
ketamine- and PCP-mediated cognitive deficits by D2 receptor
antagonists may involve indirect mechanisms, whereby D2 receptors
localized presynaptically on nondopaminergic terminals may regulate the
release of other neurotransmitters, such as acetylcholine or glutamate,
that sustain this behavioral disruption.
It should be emphasized that the present study does not discount a role
for dopamine in normal processes that subserve working memory. A
convincing body of work has established that phasic changes in dopamine
neurotransmission (as well as glutamatergic neurotransmission) occur in
the prefrontal cortex during behavioral tasks that involve working
memory (Williams and Goldman-Rakic, 1993; Wilson et al., 1994).
Although phasic activation of dopamine receptors may be a necessary
component subserving working memory, the present study suggests that a
sustained overactivation of dopamine neurotransmission by PCP is not
sufficient to deteriorate this function.
Comparison of PCP-mediated locomotor and neurochemical effects
Local infusion of PCP into the nucleus accumbens increases
locomotor activity (McCullough and Salamone, 1992), and lesions of
dopamine innervation of the nucleus accumbens (French, 1986; Steinpreis
and Salamone, 1993) or dopamine D2 receptor antagonists (Freed et al.,
1980; Castellani and Adams, 1981; Kitaichi et al., 1994; Ogren and
Goldstein, 1994) reduce PCP-induced locomotion. These findings have
strongly implicated mesoaccumbens dopamine neurotransmission in the
locomotor activating effects of PCP. However, the present observation
of a temporal dissociation between increases in dopamine release in
nucleus accumbens (or prefrontal cortex) and locomotor activation does
not support the idea that activation of dopamine neurotransmission by
PCP is sufficient to sustain locomotor activity.
Although dopamine projections to the ventral striatum have been
classically thought to play a major role in sustaining locomotor activity (Kelly and Iversen, 1976; Koob et al., 1978), the present finding of a functional dissociation between locomotor and dopaminergic effects of PCP may not be considered novel; previous findings had
clearly established that NMDA receptor antagonists produce hyperlocomotion in an apparent absence of dopaminergic activity and,
therefore, dopamine neurotransmission is not necessary to sustain
locomotor activation by this class of drugs (Carlsson and Carlsson,
1989; Druhan et al., 1996; Waters et al., 1996) or other
psychostimulants (Kuczenski and Segal, 1989; Kuczenski et al., 1997).
The novel aspect of the present findings is that this is the first
evidence, to our knowledge, demonstrating that activation of dopamine
neurotransmission is not sufficient to sustain locomotor activity. This
observation has two implications: (1) it provides additional support
for the idea that the role of dopamine in regulating the ventral
striatal neurons that subserve locomotion may be indirect and secondary
to glutamatergic involvement (Druhan et al., 1996; Waters et al.,
1996); and (2) assuming that rodent hyperlocomotion may reveal a
propensity to elicit psychosis in man, the dissociation of dopaminergic
and locomotor activation after PCP is in agreement with case reports
and unpublished clinical trials indicating that dopamine antagonists do
not improve the symptoms of psychosis produced by PCP (Perry, 1975;
Burns and Lerner, 1976) or ketamine (A. K. Malhotra, personal
communication).
Conclusions
The present findings demonstrate a temporal discordance between
increased dopamine release in the prefrontal cortex and nucleus accumbens and two behavioral effects of PCP that previously were thought to be associated with dopaminergic activation in these regions.
Specifically, <2 hr after animals received PCP, dopamine and glutamate
levels remained elevated well above baseline in the nucleus accumbens
and prefrontal cortex, whereas hyperlocomotion and impaired performance
in a discrete delayed alternation task, a rodent working memory task,
subsided. While functional expression of activated glutamate
neurotransmission is expected to diminish rapidly because of
desensitization of non-NMDA receptors, dopamine receptors generally do
not undergo rapid desensitization. Hence, the present findings indicate
that increases in synaptic availability of dopamine is not sufficient
to sustain the hyperlocomotion or cognitive deficits produced by PCP
and that nondopaminergic mechanisms are necessary for expression of
these behavioral disruptions. These findings further suggest that
targeting receptors other than dopamine receptors, in particular
metabotropic glutamate receptors that may normalize the glutamatergic
activation produced by PCP (and ketamine); may be a more effective
strategy to reduce psychotomimetic and mnemonic effects of NMDA
receptor antagonists.
| |
FOOTNOTES |
Received March 27, 1998; revised May 5, 1998; accepted May 7, 1998.
This work was supported by National Institute of Mental Health Grants
MH48404 and MH44866 and the Veterans Administration Center for
Schizophrenia.
Correspondence should be addressed to Dr. Bita Moghaddam, Department of
Psychiatry, Yale University School of Medicine, Veterans Administration
Medical Center 116A/2, West Haven, CT 06516.
| |
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Top
Abstract
Introduction
