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Vol. 289, Issue 2, 1000-1006, May 1999
Department of Psychiatry, State University of New York at Stony Brook, Stony Brook, New York
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Repeated exposure of rats to the psychotomimetic drug phencyclidine
(PCP) markedly increased the response of prefrontal cortical neurons to
the glutamate agonist N-methyl-D-aspartate
(NMDA) relative to agonist
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. Moreover, acute
challenge by PCP produced a significantly reduced block of NMDA-induced
current. In addition, the subchronic administration of PCP reduced
significantly the paired-pulse facilitation, accompanied by a
significant increase of excitatory postsynaptic current variance. These
results suggest that repeated exposure to PCP increased evoked release
of excitatory amino acids. The enhanced release of excitatory amino
acids evoked by NMDA could explain, at least partly, a hypersensitive
response to NMDA and a reduced blockade of the NMDA responses by a PCP
challenge in rats exposed repeatedly to PCP. Pretreatment with the
atypical antipsychotic drug clozapine, but not the typical
antipsychotic drug haloperidol, attenuates the repeated PCP-induced
effect. Our results support the hypothesis that clozapine may
facilitate NMDA receptor-mediated neurotransmission to improve
schizophrenic-negative symptoms and cognitive dysfunction. This novel
approach is useful for evaluating the cellular mechanisms of action of
atypical antipsychotic drugs.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Phencyclidine [PCP, a noncompetitive antagonist
of N-methyl-D-aspartate (NMDA)
receptors]-induced psychotomimetic state has been suggested to be the
best pharmacological model of schizophrenia (Deutsch et al., 1989
;
Carlsson and Carlsson, 1990; Wachtel and Turski, 1990; Javitt and
Zukin, 1991; Olney and Farber, 1995; Jentsch et al., 1997a,b; Wang and
Liang, 1998a). A single injection of PCP can induce transient clinical
symptoms of schizophrenia in humans; repeated injection can result in a
long-lasting syndrome including hallucinations, delusions, formal
thought disorder, and cognitive impairment (Cosgrove and Newell, 1991;
Javitt and Zukin, 1991). PCP and its congener ketamine also exacerbate
preexisting symptoms in schizophrenics (Pearlson, 1981; Javitt and
Zukin, 1991; Krystal et al., 1994; Malhotra et al., 1996). PCP and
other noncompetitive NMDA receptor antagonists, such as ketamine and dizocilpine (MK-801), induce an increase in locomotor activity and
stereotyped behavior (Schmidt, 1994; Sturgeon et al., 1982) and impair
learning, memory, and cognition in mice, rats, and monkeys (Danysz et
al., 1988; Alessandri et al., 1989; Boyce et al., 1991; Verma and
Moghaddam, 1996; Jentsch et al., 1997a,b). These observations form the
foundation for the glutamate hypothesis of schizophrenia which
highlights NMDA receptor hypofunction, in addition to dysfunction of
dopamine receptors, as a key mechanism underlying major aspects of
schizophrenia, particularly cognitive dysfunction (Carlson and Carlson,
1990; Javitt and Zukin, 1991; Jentsch et al., 1997a,b; Olney and
Farber, 1995).
The prefrontal cortex has been implicated in the pathophysiology of
schizophrenia (Goldman-Rakic and Selemon, 1997). Cognitive deficit, a
core feature of schizophrenia, has been observed, in particular, in
long-term PCP abusers (Cosgrove and Newall, 1991) and in rats and
monkeys repeatedly exposed to PCP (Jentsch et al., 1997a,b). The
cognitive tests for the rats and monkeys include the delayed
alternation T-maze and performance of the object retrieval with a
detour task (Jentsch et al., 1997a,b). The chronic PCP-induced cognitive dysfunction could be improved by the atypical antipsychotic drug (APD) clozapine (Jentsch et al., 1997a). Moreover,
clozapine, but not the typical APD haloperidol, blunts NMDA
antagonist-induced psychosis (Lahti et al., 1995; Malhotra et al.,
1997). Consistent with these observations, clozapine, olanzapine, and
M100907 [a purported atypical APD and the selective serotonin
5-hydroxytryptamine type2A receptor antagonist (Kehne et
al., 1996)], but not haloperidol or raclopride, facilitate NMDA
receptor-mediated transmission (Arvanov et al., 1997; Arvanov and Wang,
1997) and prevent acute PCP-induced blockade of NMDA responses in
pyramidal cells of the rat medial prefrontal cortex (mPFC; Wang and
Liang, 1998a,b). The aim of this present study was to determine whether
repeated exposure of rats to PCP alters NMDA receptor-mediated
transmission in cortical slices from control and PCP-treated rats and
whether clozapine and haloperidol could prevent the subchronic
PCP-induced effect.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Drug Administration.
Various groups of male Sprague-Dawley
rats (60-250 g) received the following treatment: 1) vehicle, 1 week/48 to 60 h (1 ml/kg i.p., b.i.d. for 1 week, 48- to 60-h
withdrawal, n = 15); 2) PCP, 1 week/48 to 60 h (2 mg/kg i.p., b.i.d. for 1 week, 48- to 60-h withdrawal,
n = 18), 3) PCP 1 week/1 week (2 mg/kg i.p., b.i.d. for
1 week, 1-week withdrawal, n = 6); 4) PCP, 1 week/0.5 h
(2 mg/kg i.p., b.i.d. for 1 week, 0.5-h withdrawal, n = 6); and 5) PCP, single/48 h (single i.p. injection of PCP 5 mg/kg, 48-h
withdrawal, n = 6). In case of cotreatment with
haloperidol (0.5 mg/kg daily, 2 weeks, n = 6) or
clozapine (25 mg/kg daily, 2 weeks, n = 6), rats
received i.p. injections of APD for 1 week, then APD plus PCP (2 mg/kg
b.i.d.) for the following week, and were sacrificed 48 to 60 h
after the last PCP injection. The dose of PCP was selected based on
those reported in the literature (Verebey et al., 1981; Sturgeon et
al., 1982; Jentsch et al., 1997a,b; Sams-Dodd, 1998) and our
observation of marked increase in locomotor activity and stereotypy
induced by PCP. As has been reported previously (Manallack et al.,
1989), there was an apparent tolerance in the aforementioned behavioral
effects produced by repeated PCP injection. The doses of clozapine and
haloperidol were selected because we have previously demonstrated that
subchronic treatment of rats with either clozapine or haloperidol at
these doses produced a "depolarization block" of spontaneously
active dopamine neurons in the midbrain (White and Wang, 1983a,b).
Preparation of Slices of the mPFC.
The procedures for
preparation of rat mPFC brain slices have been described previously
(Yang et al., 1996; Arvanov and Wang, 1997; Arvanov et al., 1997; Wang
and Liang, 1998a). Briefly, rats were decapitated under halothane
anesthesia and their brains were removed and cooled in ice-cold
artificial cerebrospinal fluid (ACSF). The coronal (transverse) slices
of mPFC (450-µm thick) were cut in ice-cold ACSF containing 117 mM
NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2,
25 mM NaHCO3, 1.2 mM NaH2PO4, and 11 mM D-glucose, aerated with 95% O2/5%
CO2 (pH 7.4). The brain slices were kept in ACSF at room
temperature for at least 1 h to allow for recovery. A single slice
was then transferred to a recording chamber (32°C) where it was kept
submerged in-between two nylon nets. The chamber was continuously
perfused with ACSF at a constant rate of 2 ml/min.
Intracellular Recording and Single-Electrode Voltage-Clamp.
Standard intracellular and single-electrode voltage-clamp recording
techniques were used to record pyramidal cells in layers V and VI of
the mPFC in slice preparations as described previously (Arvanov and
Wang, 1997, 1998; Arvanov et al., 1997; Wang and Liang, 1998a).
Intracellular recordings were performed using 4 M potassium acetate- or
3 M KCl-filled microelectrodes (tip resistance, 60-90 M
) with an
Axoclamp 2B (Axon Instruments, Burlingame, CA) amplifier. In
current-clamp mode, the bridge balance was continually monitored and
adjusted as necessary. Single-electrode voltage clamp was achieved
under discontinuous mode at a sampling rate of 5 to 6.2 KHz (30% duty
cycle), a gain of 2.5 to 5 nA/mV. The efficacy of voltage clamp,
electrode "settling time," and input capacitance neutralization at
the head stage were continuously monitored on an oscilloscope. Current
and voltage records were acquired using the software pClamp 6 (Axon
Instruments), filtered at 1 KHz, and analyzed off-line. Voltage and
current signals were also recorded on a Gould (Cleveland, OH) Easy
Graph Thermal Recorder (TA 240) and two-channel video tape recorder
(Instrutech VR-10B Digital Data Recorder, Elmont, NY).
). As it has been pointed out, these problems faced
during single-electrode voltage clamp may be less acute when dealing
with the relative changes following drug application (Madison et al.,
1987; Schweitzer et al., 1993).
The electrophysiological criteria we used for distinguishing presumed
pyramidal versus nonpyramidal cells have been previously published (see
Yang et al., 1996; Arvanov et al., 1997; Arvanov and Wang, 1998). In
general, the pyramidal cells exhibit a longer spike duration (
1 ms at
half-maximum spike amplitude) than that of interneurons and show
pronounced spike-frequency adaptation in response to constant-current
depolarizing pulses. In contrast, interneurons exhibit a brief duration
of their action potentials and lack pronounced spike-frequency
adaptation. In each neuron recorded, the membrane properties (e.g., see
Table 2) were determined in the normal ACSF using the current-clamp
mode of Axoclamp-2B amplifier. Tetrodotoxin (0.5 µM, to block action
potentials) and glycine (1 µM, to maximize NMDA induced current) were
then included in the perfusion medium, and single-electrode voltage
clamp (Vh = 
60 mV) was used to study NMDA- and AMPA-induced
current responses.
APDs were added to the perfusing ACSF. NMDA was applied by placing a
10-µl drop of 1 or 2 mM solution (with 1:100 dilution factor) on a
marked spot in the inflow channel (Rainnie et al., 1994; Zheng and
Gallagher, 1995; Holmes et al., 1996; Arvanov et al., 1997; Arvanov and
Wang, 1998; Wang and Liang, 1998a). AMPA was applied by placing a
10-µl drop of 0.5 or 1 mM solution (with 1:100 dilution factor) on a
marked spot in the inflow channel. Repeated microdrop application of
NMDA to the same pyramidal cell with an interapplication interval of
approximately 15 min produced a consistent inward current, although the
baseline current caused by NMDA may vary from cell to cell. Peak
amplitude of responses to sequential applications of two concentrations
of NMDA and AMPA was examined and response ratios were determined for
each neuron recorded.
We have examined the effect of perfusion of NMDA on pyramidal cells of
the mPFC. Bath application of 10 µM NMDA for 3 min evoked a gradual
increase of inward current. It often took 3 to 4 min to reach the
plateau; it is difficult to obtain a true maximum due to
excitotoxicity, desensitization, and/or incomplete equilibrium. Moreover, it required 25- to 30-min interapplication intervals to avoid
an obvious desensitization and maintain a stable baseline. Thus, it is
rather impractical to study the drug effect on NMDA current using this
method. We have also tried the micropressure injection of NMDA. It is
much more difficult to estimate the actual concentration of drug and to
maintain a stable baseline by using the technique of micropressure
injection. Whereas applying negative pressure to the pipette causes
dilution of the drug solution in the pipette, without using retaining
pressure, NMDA slowly diffuses out of the pipette and causes receptor desensitization.
Excitatory postsynaptic currents (EPSCs) were elicited by passing two
identical rectangular current trials (0.05-ms pulse width, 15-25-µA
pulse strength, 40 ms of the interpulse interval) between the tips of a
bipolar stainless steel electrode placed in the medial part of the
forceps minor, about 1 mm from the recording site. EPSCs were recorded
by the electrodes filled with 2 M CsCl plus 25 mM QX 314 (lidocaine
N-ethyl bromide quaternary salt, tip resistance 30-50 M)
to improve the space clamp and to block voltage-activated
Na+ and K+ channels. Under these conditions,
the membrane resistance was usually increased by 30 to 50% (Wuarin et
al., 1992). Sixty response traces per epoch were collected and
statistical analyzed using pClamp-6 Spike Data Analyses Systems
(Arvanov and Wang, 1998).
Data Analysis. The results were presented as mean ± S.E.M. paired t test, Student's t test, ANOVA, and least-significant difference post hoc comparison were used; 0.01 and 0.05 were selected for testing the level of significance.
Drugs.
The compounds
(±)--amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA),
NMDA, QX 314 and tetrodotoxin were all purchased from Research
Biochemicals International (Natick, MA). PCP, clozapine, and
haloperidol were generous gifts from National Institute of Drug Abuse,
Sandoz (Hanover, NJ), and McNeil Laboratories (Fort Washington, PA), respectively.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Ratios of NMDA/AMPA.
To avoid a marked variation of NMDA
responses evoked in different slices, we have adapted the techniques of
Beart and Lodge (1990) with a modification. We have examined the ratios
of peak currents induced by sequential applications of two
concentrations of NMDA and AMPA in each neuron (Table
1; Fig. 1).
The concentrations of NMDA (10 and 20 µM) and AMPA (5 and 10 µM)
were chosen based on previous experiments (Arvanov et al., 1997;
Arvanov and Wang, 1998; Wang and Liang, 1998a) and because they
produced a submaximal response. AMPA-induced responses were used as a
reference because PCP should not interact directly with the AMPA
subtype of glutamate receptors. Indeed, this is supported by the fact
that the AMPA10/AMPA5 ratio was unchanged in
all PCP-treated groups, i.e., the ratios were not significantly
different from that of the vehicle control group (Table 1). This
normalization of data would minimize daily variations and differential
sensitivities among cells.
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Effect of Subchronic PCP Treatment on Ratios of NMDA/AMPA and PCP
Challenge.
Among groups of animals receiving PCP treatment, a
statistically significant increase of
NMDA20/NMDA10 and
NMDA20/AMPA5 ratios was found in rats receiving
1-week repetitive treatments with PCP (2 mg/kg i.p., b.i.d.) followed
by a 48- to 60-h withdrawal period (1 week/48-60 h). Our results
suggest that subchronic administration of PCP induced the development
of a hypersensitive response of the cortical neurons to NMDA. This view
is further supported by the finding that an acute challenge of PCP
produced a significantly diminished blockade of NMDA-induced inward
current in cells recorded from the PCP 1-week/48- to 60-h group (Table
1). The trend for augmentation of the ratios of
NMDA20/NMDA10 and
NMDA20/AMPA5 still persisted in rats for 1 week
after the cessation of subchronic PCP treatment, although the augmented
ratios failed to reach statistical significance. This was also true in
the case of rats which received only a single PCP injection (5 mg/kg
i.p.). These observations suggest that 1) subchronic treatment with PCP
is more effective than a single injection of PCP to produce a
hypersensitive response of neurons in the mPFC to NMDA, and 2) the
subchronic PCP-induced hypersensitive response of mPFC cells to NMDA is
relatively long-lasting. Interestingly, in the group receiving
repetitive treatment with PCP but only a 0.5-h withdrawal period, the
NMDA20/NMDA10 ratio was not significantly
different from that of the vehicle control group. This observation
suggests that the residual PCP, which is highly lipophilic (Misra et
al., 1979), may have partially blocked the NMDA receptor channel and
obscured the hypersensitive response.
Effect of Subchronic PCP Treatment on Paired-Pulse Facilitation (PPF). To investigate at the cellular level whether repeated exposure to PCP may affect the presynaptic processes, we examined and compared the PPF of evoked EPSCs in PCP 1-week/48- to 60-h and vehicle 1-week/48- to 60-h groups (Fig. 1C). The PPF (EPSC2/EPSC1) value for the vehicle control and PCP groups was 1.8 ± 0.1 (n = 21) and 1.1 ± 0.1 (n = 13), respectively. The difference of the PPF values between the two groups was statistically significant (t test, p < .05). This decrease of PPF in PCP-treated rats was associated with an increase (207 ± 61% of controls, p < .05) in EPSC variance (mCV = mean2/[SD]2). These results suggest that repeated exposure to PCP increases the evoked release of excitatory amino acids (EAAs).
Corresponding to the aforementioned results, there was a significant depolarization of membrane potential and a significant reduction of the spike frequency adaptation and slow after hyperpolarization (sAHP) in PCP 1-week/48- to 60-h rats compared with vehicle controls (Table 2). However, other membrane properties such as neuronal input resistance, spike amplitude, and half-width were not significantly altered. Thus, an increase in the NMDA/AMPA response ratio observed in PCP-treated rats was not due to changes of membrane input resistance. We cannot rule out the possibility that membrane depolarization at the dendritic site (which could have escaped the voltage clamp) may contribute to the higher NMDA/AMPA ratio. However, the neurons recorded from PCP-treated animals that exhibited resting membrane potentials in a range from70 to 73 mV, i.e.,
close to controls, still displayed the significant increased NMDA/AMPA
ratio (n = 7, p < .05). This argues
against the view that the slightly depolarized level of resting
membrane potential in PCP-treated animals was the sole mechanism for
facilitation of NMDA responses. Rather, this may result from the
enhanced release of EAAs and functional hyperactivity of NMDA
receptor-mediated transmission in the prefrontal cortex.
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Effect of Clozapine versus Haloperidol on Subchronic PCP-Induced Alteration of Ratios of NMDA/AMPA. To determine whether APDs may prevent the effects produced by the subchronic PCP treatment, we pretreated rats for 1 week with either clozapine (25 mg/kg/day i.p.) or haloperidol (0.5 mg/kg/day i.p.) alone and the following week cotreatment of either APD with PCP. As shown in Table 3, clozapine prevented the subchronic PCP-induced enhancement of both NMDA20/NMDA10 and NMDA20/AMPA5 ratios. Although there was a tendency for haloperidol to reduce subchronic PCP-induced enhancement of NMDA20/NMDA10 and NMDA20/AMPA5 ratios, the reduction did not reach statistical significance. Overall, there was not a significant difference between the clozapine and haloperidol groups on ratios of NMDA and AMPA (p > .05, t test), although the difference of NMDA20/NMDA10 ratios between the two groups is quite substantial (p < .05, t test).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The results from the present study demonstrate that repetitive treatment of rats with PCP for 1 week produces a significant increase of neuronal responses to NMDA relative to AMPA in the prefrontal cortical brain slices. The trend for augmentation of the ratios of NMDA20/NMDA10 and NMDA20/AMPA10 still persisted in rats for 1 week after the cessation of subchronic PCP treatment, suggesting the effect produced by repeated PCP treatment is relatively long-lasting. On the other hand, in the group receiving repetitive treatment with PCP but only a 0.5-h withdrawal period, the NMDA20/NMDA10 ratio was not significantly different from that of the vehicle control group. It was the same in the group of rats that received only a single injection of PCP with a 48- to 60-h withdrawal period. Although there was a trend of increase of the ratios of NMDA20/NMDA10 and NMDA20/AMPA10 in the single injection group, the increase of the aforementioned ratios did not reach statistical significance. Taken together, these results indicate that 1) repeated treatment with PCP is more effective than a single injection to produce a hypersensitive response of mPFC cells to NMDA, and 2) the residual PCP in the system could not explain the hypersensitive response of cortical cells to NMDA. In fact, in the group receiving repetitive treatment with PCP but only a 0.5-h withdrawal period, the residual PCP may have partially blocked the NMDA receptor channel and obscured the hypersensitive response.
In agreement with our findings, McDonald et al. (1990) have reported
that MK-801 pretreatment induces rapid and persistent up-regulation of
NMDA receptors and sensitizes the brain to NMDA-induced brain injury in
rats. Furthermore, Williams et al. (1992) demonstrated that repeated,
but not after 1 day, exposure to
D()2-2-amino-5-phosphonopentanoid acid
(D-AP5) up-regulated NMDA but not AMPA receptors in
cultured cortical neurons of rats. However, it should be pointed out
that the results obtained from receptor-binding studies remain
controversial. For example, it has been reported that repeated exposure
to PCP or MK-801 could either increase the binding capacity
Bmax of [3H]tenocylidine
(TCP) to cerebral cortical membranes of mice (Saransaari et al.,
1993) or decrease Bmax of [3H]PCP
in the olfactory bulbs of the rat (Quirion et al., 1982). Some studies
have demonstrated that even a single injection of PCP or MK-801 was
effective in increasing the Bmax of NMDA
receptors in the rat hippocampus (Gao and Taminga, 1994, 1995).
Moreover, Manallack et al. (1989) have shown that subchronic
administration of MK-801 in the rat decreases cortical binding of
[3H]D-AP5 but not that of
[3H]TCP, suggesting that the NMDA primary acceptor site
is being independently regulated relative to the PCP sites, at least in response to long-term blockade of the ion channel. The different treatment paradigms (with various NMDA receptor antagonists, different doses, and length of treatment) in different species and various ligands and tissues used for the assay in these studies may contribute to the inconsistent results.
The functional hyperactivity of NMDA receptors might be a homeostatic
compensatory response to the prolonged blockade of the NMDA receptor
channel by PCP. It is possible that prolonged blockade of NMDA
receptors in presynaptic glutamatergic terminals (Connick and Stone,
1988; Montague et al., 1994; Berretta and Jones, 1996; Arvanov and
Wang, 1997) and/or in the somadendridic site of the pyramidal cell
could have triggered the PCP-induced up-regulation of NMDA receptors.
Reminiscent of up-regulated NMDA receptors induced by subchronic PCP
treatment, increased expression of the NMDAR1 receptor subunit and NMDA
receptors have been observed in the post-mortem brain of alcoholics and
in rats exposed repeatedly to ethanol or pentobarbital (Freund and
Anderson, 1996; Chen et al., 1997; Tanaka et al., 1997; Oh et al.,
1997). Therefore, the augmented expression of NMDA receptors could
represent a compensatory response to the inhibitory action of PCP,
ethanol, or pentobarbital on the neuronal NMDA receptors.
Interestingly, the enhanced response of pyramidal cells to NMDA in the
PCP-treated animals was accompanied by the decrease of PPF and increase
of mCV of the electrically evoked EPSCs. Such a decrease of
PPF and increase of mCV is known to be associated with
conditions where presynaptic transmitter release is enhanced (Hess et
al., 1987; Malinow and Tsien, 1990; Arvanov and Wang, 1997). Thus, our
results suggest that repeated exposure to PCP increases presynaptic
release of EAAs evoked by electrical stimulation of the forceps minor,
which could be the result of up-regulated NMDA autoreceptors (Connick
and Stone, 1988; Montague et al., 1994; Berretta and Jones, 1996;
Arvanov et al., 1997). If this is the case, application of NMDA should
also enhance the release of EAAs (Montague et al., 1994; Berretta and
Jones, 1996; Arvanov et al., 1997) and this could explain, at least in
part, the hypersensitive response of mPFC pyramidal cells to NMDA.
Furthermore, the released EAAs, in turn, act primarily on postsynaptic
non-NMDA receptors and cause membrane depolarization (Arvanov and Wang,
1998; Wang and Liang, 1998a). It is known that the blockade of the NMDA
receptor channel by PCP and analogs is voltage-dependent and the
recovery of the blockade is strikingly enhanced by continuous exposure to NMDA (Honey et al., 1985; Huettner and Bean, 1988; MacDonald et al.,
1987). Therefore, an enhanced release of EAAs by NMDA could also
account for a reduced blockade of the NMDA responses by a PCP challenge
in rats receiving repetitive PCP treatment.
Interestingly, clozapine, but not haloperidol, was found to prevent the
subchronic PCP-induced functional hyperactivity of NMDA receptors. In
consonant with our results, chronic treatment with clozapine
significantly decreased MK-801 binding in the mPFC (Terazi et al.,
1996; McCoy and Richfield, 1996; Giardino et al., 1997) and decreased
the expression of NR-2C subunits of the NMDA receptor (Riva et al.,
1997). This decrease of the expression of NMDA receptors might be a
compensatory reaction to the facilitating effect of clozapine on NMDA
receptor-mediated transmission (Arvanov et al., 1997); this effect may
contribute to the ability of clozapine to nullify the functional
hyperactivity of NMDA receptors in rats exposed repetitively to PCP.
It should be pointed out, however, that subchronic haloperidol
treatment also significantly reduced [3H]MK-801 binding
in the mPFC (Terazi et al., 1996). Moreover, our preliminary results
showed that subchronic treatment with either clozapine or haloperidol
induced a marked hyposensitive response of pyramidal cells in the mPFC
to NMDA (Wang et al., 1998). The present results show that there was a
tendency for haloperidol to reduce subchronic PCP-induced enhancement
of NMDA20/NMDA10 and
NMDA20/AMPA5 ratios, although the reduction of
the ratios did not reach statistical significance. Obviously, further
studies are needed to elucidate the mechanisms by which clozapine but not haloperidol prevents the hypersensitive responses to NMDA in
pyramidal cells of the mPFC in rats that have been treated repeatedly
with PCP. Additionally, the action of other putative typical and
atypical APDs on PCP-induced effect should also be examined and compared.
We have previously shown that clozapine, olanzapine, and M100907, but
not haloperidol or raclopride, prevent acute PCP-induced blockade of
NMDA responses in pyramidal cells of the mPFC (Wang and Liang,
1998a,b). In the present study, we have further demonstrated that
clozapine but not haloperidol prevents subchronic PCP-induced hypersensitive NMDA responses. Consistent with our findings, it has
been demonstrated that clozapine, but not haloperidol, blunts NMDA
antagonist-induced psychosis (Lahti et al., 1997; Malhotra et al.,
1997) and that clozapine effectively ameliorates subchronic PCP-induced
impairment of the cognitive performance in monkeys (Jentsch et al.,
1997a).
In summary, repeated administration of PCP and electrophysiological detection of the ratio of NMDA/AMPA responses in the cortical slices may be useful for exploring the cellular mechanisms by which PCP produces its psychotomimetic effect, particularly cognitive dysfunction. With additional studies, this may prove to be a new electrophysiological model for screening and evaluating therapeutic agents targeted for neurological and psychiatric disorders associated with cognitive impairment.
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Acknowledgments |
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We thank Drs. D. Bleakman and D. Lodge for reading an earlier version of the manuscript and helpful discussions. We also thank National Institute of Drug Abuse, Sandoz, and McNeil Laboratories for their gifts of PCP, clozapine, and haloperidol, respectively.
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Footnotes |
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1 This research was supported by U.S. Public Health Service Grant MH-41440.
Send reprint requests to: Rex Y. Wang, Ph.D., Department of Psychiatry and Behavioral Sciences, SUNY, Putnam Hall, South Campus, Stony Brook, NY 11794-8790. E-mail: rex.wang{at}sunysb.edu.
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Abbreviations |
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PCP, phencyclidine;
ACSF, artificial
cerebrospinal fluid;
AMPA, (±)--amino-3-hydroxy-5-methylisoxazole-4-propionic acid;
APD, antipsychotic drug;
EAA, excitatory amino acid;
EPSC, excitatory
postsynaptic current;
mcv EPSC variance = Mean2/[SD]2, MK-801, dizocilpine;
mPFC, medial prefrontal cortex;
NMDA, N-methyl-D-aspartate;
PPF, paired-pulse
facilitation.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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implications for schizophrenia and Parkinson's disease.
Trends Pharmacol Sci
13:
272-276.This article has been cited by other articles:
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  G. E. Duncan, S. Miyamoto, and J. A. Lieberman Chronic Administration of Haloperidol and Olanzapine Attenuates Ketamine-Induced Brain Metabolic Activation J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 999 - 1005. [Abstract] [Full Text] [PDF]
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 J. D. Jentsch, J. R. Taylor, and R. H. Roth Phencyclidine Model of Frontal Cortical Dysfunction in Nonhuman Primates Neuroscientist, August 1, 2000; 6(4): 263 - 270. [Abstract] [PDF]
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G. E. Duncan, S. Miyamoto, J. N. Leipzig, and J. A. Lieberman Comparison of the Effects of Clozapine, Risperidone, and Olanzapine on Ketamine-Induced Alterations in Regional Brain Metabolism J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 8 - 14. [Abstract] [Full Text]
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denotes that the result of the CLOZ + PCP group is
significantly different from those of the PCP 1-week/48- to 60-h group
(p < .05; see Tables