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BEHAVIORAL PHARMACOLOGY
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania (G.G.K., M.B., P.J.C.); and Behavioral Pharmacology, San Diego, California (U.C.C., L.M.H., D.R., L.J.B.)
Received January 2, 2003; accepted March 20, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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). This
observation has led to the hypothesis that NMDAR hypofunction may be
critically involved in the etiology and/or underlying symptoms of
schizophrenia (Olney et al.,
1999). In support of this hypothesis, enhancement of NMDAR density
has been reported in a variety of brain regions of schizophrenic patients
(Ishimaru et al., 1992,
1994). Furthermore,
enhancement of NMDAR function through administration of agonists at the
allosteric glycine binding site results in a significant symptomatic
improvement in schizophrenic patients
(Javitt et al., 1994;
Goff et al., 1995;
Heresco-Levy et al., 1996,
1999,
2002;
Tsai et al., 1998).
Metabotropic glutamate receptors (mGluR) are seven-transmembrane G
protein-coupled receptors. There are currently eight known mGluR subtypes
divided into three groups based on their homology, pharmacology, and second
messenger coupling. Group I mGluRs (mGluR1 and mGluR5) couple to Gq and
stimulate phosphoinositide hydrolysis (for review, see
Conn and Pin, 1997). Clinical
studies suggest that mGluR5 allele frequency is associated with schizophrenia
among certain cohorts (Devon et al.,
2001) and that a modest, yet significant, increase in mGluR5
message is found in cortical pyramidal cell layers of schizophrenic brains
relative to controls (Ohnuma et al.,
1998).
Preclinically, activation of group I mGluRs potentiates NMDAR-mediated
function in a variety of brain regions and this activity is often mediated by
mGluR5 (Awad et al., 2000;
Mannaioni et al., 2001;
Pisani et al., 2001;
Benquet et al., 2002). Among
mGluRs, this effect seems to be specific for group I mGluRs in that activation
of group II or III mGluRs has no effect on NMDAR-mediated currents in vitro
nor do group I agonists have any affect on
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated
currents (Pisani et al.,
1997). These clinical and preclinical findings have led
investigators to hypothesize that activation of mGluR5 may normalize
hypofunctional NMDAR-mediated activity and thereby represent a useful approach
for the development of novel antipsychotic drug treatments
(Chavez-Noriega et al., 2002;
Marino and Conn, 2002).
Prepulse inhibition (PPI) of the acoustic startle response is an easily
measured, quantifiable behavior that is disrupted in animals after the
administration of dopamine agonists or NMDAR antagonists (for review, see
Geyer et al., 2001). Because
PPI is deficient in schizophrenic patients, this assay has been proposed to
model the sensorimotor gating deficits observed in schizophrenic patients
(Braff and Geyer, 1990). A
recent report suggests that administration of the mGluR5 selective
use-dependent antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) can
potentiate PCP-induced deficits in PPI in rats
(Henry et al., 2002) at doses
of MPEP that have no effect alone (Spooren
et al., 2000; Henry et al.,
2002). Furthermore, preliminary reports suggested that mGluR5
knockout mice may be deficient in PPI
(Geyer et al., 2000). More
recent reports, however, suggest that this may not be a reliable finding
(O'Meara et al., 2002).
To more thoroughly describe the role of mGlu5 receptors in rodent behavior, the current study examined 1) the role of the mGluR5 antagonist MPEP in multiple schizophrenia-related animal models after acute PCP treatment; 2) mGluR5 knockout mice in a PPI assay; and 3) the effect of the selective mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) on PPI under normal conditions and after amphetamine-induced disruption of PPI.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Locomotor Activity. Activity was assessed as mean distance traveled (in centimeters) in standard 16 x 16 photocell testing chambers measuring 43.2 cm (length) x 43.2 cm (width) x 30.5 cm (height) (MED Associates, St. Albans, VT). Animals were habituated to individual activity chambers for at least 60 min before PCP administration. After administration of PCP or vehicle, activity was recorded for a 3-h time period. Data are expressed as the mean ± S.E.M. distance traveled recorded in 10-min intervals over the test period. The data were analyzed using repeated measures analysis of variance followed by post hoc testing using Tukey's honestly significant difference test, when appropriate. A difference was considered significant when p ≤ 0.05.
Prepulse Inhibition. SR-LAB (San Diego Instruments, San Diego, CA)
acoustic startle chambers were used in the present studies. SR-LAB software
controlled the delivery of all stimuli to the animals and recorded the
response. Startle amplitude was measured as the mean value during a 65-ms
period beginning at the onset of the startle-eliciting stimulus for mouse
studies and during a 100-ms period for rat studies. Before the first session
of any day the chambers were calibrated for both movement, using equipment
provided by SR-LABS, and for sound levels, using a Tandy brand sound level
meter. In each session, animals were randomly assigned to an experimental
group, received their appropriate treatment, and were placed in the chambers.
Animals were given a 5-min acclimation period during which a 65-db background
noise was continuously present. This background noise remained present
throughout the entire testing session. After the acclimation period, animals
received a series of five 40-ms, 118- to 120-db bursts of white noise to
partially habituate the animals to the startle-eliciting stimulus
(Davis, 1988). After these
five presentations, the test session, which consisted of 10 repetitions of
trials, began. For mouse PCP/MPEP combination studies, six different trial
types were presented during the session. These consisted of the following: a
10-ms prepulse at 75 or 80 db followed 100 ms later by the 118- to 120-db,
40-ms startle pulse (prepulse pulse conditions), the startle pulse alone
(pulse alone), a period where no stimulus was presented (nostim), and the
10-ms, 75- or 80-db prepulse (i.e., 10 or 15 db above background) presented by
itself (prepulse alone). Rat PCP/MPEP combination studies were performed in
the same manner; however, a 70-db prepulse intensity (i.e., 5 db above
background) was added to the test for this study. The mGluR5 knockout mouse
studies and the rat i.c.v. CHPG study were also performed similarly; however,
the trial types consisted of a 10-ms prepulse at 70, 75, 80, or 85 db (i.e.,
5, 10, 15, or 20 db above background) followed 100 ms later by the 118- to
120-db, 40-ms startle pulse, a pulse alone condition, and a nostim condition.
Initial and pilot studies had determined that these prepulse intensities were
insufficient to induce a significant startle response independent of the
startle stimulus. The stimuli were presented in random order with
interstimulus intervals averaging 15 s. Levels of prepulse inhibition were
determined by the formula (100 – ((prepulse pulse/pulse alone) x
100)) and expressed as percentage of prepulse inhibition ± S.E.M. Data
were analyzed using repeated measures analyses of variance with the prepulse
condition as the within group factor followed by analyses of simple main
effects and, when appropriate, post hoc analysis using the Dunnett or Tukey
test.
Drugs. PCP hydrochloride and d-amphetamine sulfate were obtained from Sigma-Aldrich (St. Louis, MO), dissolved in sterile saline, and injected at a volume of 1 ml/kg s.c. MPEP and CHPG were obtained from Tocris Cookson, Inc. (Ellisville, MO). MPEP was dissolved in sterile water or a 10%:90% Tween 80/water vehicle and injected at a volume of 1 ml/kg i.p. CHPG was dissolved in 0.5 N NaOH (pH adjusted to 7.0 with 1 N HCl) and infused into the third ventricle at a rate of 2 µl/min. For PPI experiments, MPEP was delivered 30 or 70 min pretest for mouse and rat studies, respectively. PCP was delivered 20 or 10 min pretest for mouse and rat, respectively. CHPG and amphetamine were delivered 15 and 20 min pretest, respectively. For locomotor studies, MPEP was delivered 60 min before PCP administration. Where appropriate, drug doses were determined as the base.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Prepulse Inhibition
MPEP/PCP Administration. The effect of PCP and MPEP alone, or in
combination, on PPI was tested in 129S6 mice at two prepulse intensities (5
and 10 db above background). Figure
2A depicts the effect of vehicle, PCP alone (1–10 mg/kg
s.c.), MPEP alone (3–30 mg/kg i.p.), and 10 mg/kg s.c. PCP combined with
30 mg/kg i.p. MPEP. Under these conditions, PCP, at doses up to 10 mg/kg s.c.,
did not significantly disrupt PPI at either prepulse level. MPEP, up to 30
mg/kg i.p., also had no effect on PPI by itself. When 30 mg/kg MPEP was
combined with 10 mg/kg s.c. PCP, however, a significant disruption of PPI was
observed during both prepulse conditions
(Fig. 2A). These findings were
confirmed by statistical analyses. Thus, a repeated measures analysis of
variance using prepulse level as the within factor and treatment condition as
the between factor revealed a significant main effect of treatment
[F(7,68) = 6.94, p < 0.001], but no treatment by prepulse
level interaction, suggesting that MPEP enhanced the disruptive PPI effects of
PCP regardless of prepulse level. This was further confirmed by the finding of
a significant simple main effect of treatment for each prepulse level
[F(7,68) = 6.51, p < 0.001 and F(7,68) = 6.04,
p < 0.001 for the 5- and 10-db prepulse levels, respectively].
Post hoc analysis using the Tukey procedure revealed a significant deficit in
PPI at both the 5 and 10 prepulse intensity levels relative to vehicle +
vehicle treatment when a combination of MPEP (30 mg/kg i.p.) and PCP (10 mg/kg
s.c.) was administered (p < 0.01). No significant effect on PPI
was found for either drug administered alone (p = 0.5 for MPEP,
p > 0.1 for PCP). Likewise, no significant differences were
observed during pulse alone presentations
(Fig. 2B).
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Similar to the findings using mice, we also found a significant MPEP potentiation of PCP effects on PPI in rats (Fig. 3). Thus, combining 10 mg/kg i.p. MPEP with 1 mg/kg s.c. PCP disrupted PPI, whereas neither treatment alone had any significant effect. Combination treatment resulted in a significant disruption of PPI at a prepulse level 10 or 15 db above background, whereas a similar, albeit nonsignificant, trend was noted at a prepulse level 5 db above background. These results were confirmed by the finding of a significant main effect of treatment at the 10- and 15-db prepulse levels [F(3,44) = 3.91, p <0.016 and F(3,44) = 6.07, p < 0.003, respectively]. At the 10-db level, post hoc testing using the Tukey procedure revealed a significantly enhanced disruption of PPI after MPEP + PCP treatment over PCP treatment alone; however, the disruption of PPI produced by PCP alone or combination treatment did not significantly differ from vehicle condition. At the 15-db level, post hoc testing revealed a significant reduction of PPI after combination treatment relative to both vehicle and PCP alone treatment. All other treatments failed to differ from vehicle under these conditions. As with the previous study, none of the treatments or combinations significantly altered response during pulse alone trials (Fig. 3B).
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mGluR5 Knockout Mice. Levels of PPI were tested three times in wild-type (mGluR5+/+) and knockout (mGluR5–/–) mice. Study 1 and 2 occurred within the same week, whereas study 3 occurred 10 days after the completion of study 2. The same mice were tested in all studies. The primary purpose of study 3 was to examine PPI effects under different light/dark conditions. The results of these tests are presented in Fig. 4A and demonstrate a significant and reproducible deficit of PPI in these mice. Repeated measures analysis of variance revealed a significant main effect of genotype [F(1,21) = 6.24, p < 0.03], a significant main effect of test number [F(2,42) = 6.18, p < 0.006], a significant effect of prepulse level [F(3,63) = 158, p < 0.001], but no significant prepulse level by genotype (p = 0.055) nor test number by genotype (p > 0.9) interactions. The lack of significant interactions suggest a stable deficiency of PPI in mGluR5–/– mice relative to wild-type controls that is neither dependent on prepulse intensity nor the activity phase of the animals during testing. Analysis of the simple main effect of genotype for each test revealed a significant disruption of PPI for prepulse levels 15 and 20 db above background for study 1 [F(1,23) = 5.07 and 4.74, p values < 0.04, respectively] and study 2 [F(1,23) = 7.99 and 7.92, p values = 0.01, respectively]. Similar analysis revealed a significant disruption of PPI in mGluR5–/– mice in study 3; however, this difference only reached the level of significance at the 20-db prepulse intensity [F(1,23) = 5.02, p < 0.04]. No significant differences were observed during pulse alone presentations (Fig. 5B).
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mGluR5 Agonist Treatment. Because previously discussed data
demonstrate that mGluR5 agonist treatment potentiates NMDAR function
(Mannaioni et al., 2001;
Pisani et al., 2001), it is
reasonable to expect that mGluR5 agonist administration could potentiate the
effect of a use-dependent NMDAR antagonist such as PCP. The corollary
hypothesis that mGluR5 activation should reverse the effect of PCP-mediated
behavior is also suggested by previous reports that glycine or glycine
transport inhibitors reverse the behavioral effect of PCP, presumably through
a coagonist property of glycine at the NMDA receptor
(Javitt et al., 1997). In this
way, both an enhancement and reversal of PCP-induced behavior after mGluR5
activation would be consistent with enhancement of NMDAR-mediated behaviors.
To examine the role of mGluR5 activation on PPI that was disrupted by
interaction with relevant neuronal circuitry distinct from a direct antagonism
of NMDARs, we examined the effect of the mGluR5 agonist CHPG on
amphetamine-induced disruption of PPI. The effect of multiple doses of
amphetamine (0.5–2 mg/kg s.c.) on PPI in these rats is depicted in
Fig. 5A. As expected,
amphetamine dose dependently disrupted PPI across all prepulse levels examined
as indicated by a significant main effect of dose [F(3,28) = 4.32,
p < 0.02] and the absence of a significant prepulse level by dose
interaction. The decrease in PPI was found independent of any significant
change in basal startle response (Fig.
5D). Because a dose of 2 mg/kg s.c. was found to disrupt PPI at
prepulse levels 10, 15, and 20 db above background, this dose was chosen for
interaction studies with CHPG. Figure
5B depicts the effect of CHPG (500 nmol/8 µl i.c.v.) in normal
rats. As shown, CHPG had no effect on PPI at any prepulse level. Furthermore,
CHPG had no significant effect on startle amplitude during the pulse alone
condition (Fig. 5D). In
contrast to these results, CHPG (500 nmol/8 µl i.c.v.) delivered to
amphetamine (2 mg/kg s.c.)-treated rats significantly ameliorated the
disruptive effects of amphetamine at prepulse intensities 10, 15, and 20 db
above the background level (Fig.
5C) independent of any significant change in basal startle
response (Fig. 5D). These
differences were confirmed by the finding of a significant main effect of
treatment [F(1,18) = 8.78, p < 0.009]. Analyses of simple
effects at each prepulse level revealed significant differences between
treatment conditions at the 10-, 15-, and 20-db prepulse intensities
(p values < 0.05).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The finding that MPEP has little effect by itself in locomotor or PPI
assays is consistent with a growing body of literature
(Spooren et al., 2000;
Tatarczyñska et al.,
2001; Henry et al.,
2002). In the present report, we found that, at doses up to 10 and
30 mg/kg i.p., MPEP had no activity on either locomotor activity or PPI.
Nonetheless, when MPEP was combined with PCP, we found a significant
enhancement of PCP response in each instance. These data are consistent with a
recent report by Henry et al.
(2002) where MPEP potentiated
the effect of PCP on activity and PPI in rats at doses that had no effect
alone. Despite the lack of effect of MPEP alone,
mGluR5–/– mice did show
consistent, albeit, modest deficits in PPI. Because the role of mGluR5 in
these behavioral measures is likely modulatory (see discussion below), we
suggest that complete removal of the contribution of this receptor system may
be required before any emergent behavior can be reliably measured in normal
animals. Thus, for any mGluR5 antagonist, receptor occupancy values in excess
of the 
90% expected in the present study
(Anderson et al., 2002) may be
needed to produce data consistent with
mGluR5–/– mice. However, after
pharmacological disruption of the relevant neuronal systems (e.g., using PCP
or amphetamine), the role of mGluR5 may be more pronounced and subtle
differences in behavior may then be revealed.
The potentiation of PCP activity in these animal behaviors seems to be
selective for mGluR5 antagonist application in that the mGluR2/3 agonist
LY314582 had no effect on PCP-induced responses
(Henry et al., 2002). Although
MPEP has been shown to antagonize NMDAR function in vitro
(O'Leary et al., 2000), it is
unlikely that MPEP, at these doses, augmented PCP effects via this mechanism.
First, the MPEP dose range used in the present study does not exceed doses
required for maximal in vivo mGlu5 receptor occupancy
(Anderson et al., 2002).
Second, we have found that doses of MPEP higher than those reported in the
present study result in an inconsistent decrease of spontaneous locomotor
activity in nonhabituated rats (data not shown). This effect is opposite of
the predicted activity of NMDAR antagonist activity on this behavior. Finally,
it has been reported that MPEP brain levels achieved at behaviorally active
doses are well below the concentration required to inhibit NMDA currents in
vitro (Khun et al., 2002).
Related to this latter suggestion, the dose range of MPEP used in these
studies is in line with those reported to produce mGluR5-mediated anxiolytic
effects in rats (Tatarczyñska et
al., 2001; Brodkin et al.,
2002). Thus, available data suggest that the synergistic effect of
MPEP on PCP-mediated behavior observed in the present study was due to its
primary action as an mGluR5 antagonist.
As with MPEP, it is likely that the ability of the mGluR5 agonist CHPG to
ameliorate amphetamine-induced disruption of PPI is due to selective agonist
activity at mGlu5 receptors. Thus, previous publications demonstrate a
selective mGluR5 agonist activity of CHPG at these doses using in vivo
phosphoinositide hydrolysis measures
(Johnson et al., 1999;
Anderson et al., 2002).
One way in which mGluR5 may modulate neuronal circuitry responsible for the
measured behaviors is through interaction with the NMDAR system. As discussed
previously, mGluR5 activation potentiates NMDAR function in vitro. NMDAR
activity leading to modest increases in Ca2+
concentrations can prevent mGluR5 desensitization via activation of a protein
phosphatase and subsequent dephosphorylation of the receptor
(Alagarsamy et al., 1999).
Higher internal Ca2+ concentrations, however, may
promote desensitization of mGluR5 via phosphorylation at a protein kinase
C-sensitive site (Alagarsamy et al.,
2002). These results reveal the existence of a synergistic
feedback mechanism under conditions of low-to-modest internal
Ca2+ levels. Higher Ca2+ levels
are expected to limit mGluR5 function and consequently its ability to augment
NMDAR function. These findings suggest that the role of mGluR5 on PPI and
locomotor-related preclinical behaviors, which are also sensitive to NMDAR
antagonists, might be less pronounced under conditions of normal NMDAR
function coincident with higher basal intracellular Ca2+
levels relative to conditions of NMDAR hypofunction. Consistent with this
hypothesis, we have presently demonstrated a modest effect in knockout mice, a
lack of effect of MPEP alone, and a lack of effect of CHPG in normal rats
(i.e., the role of mGluR5 was only unmasked after disruption of relevant
neuronal circuitry).
In addition to biochemical interactions, an emerging body of evidence
suggests that mGluR5 and NMDARs may also physically interact in a manner that
mediates receptor trafficking to the cell surface. Thus, NMDA receptors are
associated with the postsynaptic density protein shank, via interaction with
guanylate kinase associate proteins (Kim
et al., 1997; Naisbitt et al.,
1999). Interestingly, shank and group I mGluRs are both
homer-associated proteins, and homer proteins are known to dimerize
(Tu et al., 1998;
Xiao et al., 1998, 1999), thus
providing a physical link between mGluR5 and NMDARs. Because homer proteins
have recently been shown to regulate mGluR5 trafficking
(Ango et al., 2002), this
physical interaction between mGluR5 and NMDAR could potentially impact
signaling, receptor trafficking, or both.
The functional consequence of mGluR5 deletion on NMDA function has been
previously demonstrated. Thus, deficits in the NMDAR-mediated component of
long-term potentiation in
mGluR5–/– mice have been
described (Lu et al., 1997;
Jia et al., 1998). We
hypothesized that a more widespread modulatory role of mGluR5 on
NMDAR-mediated function would result in a modest deficit of PPI. Our finding
of reproducible deficits in
mGluR5–/– mice relative to their
wild-type controls is consistent with this hypothesis. These data are also
consistent with deficits previously reported in abstract form by Geyer et al.
(2000). However, this finding
is inconsistent with abstract reports by other groups
(O'Meara et al., 2002). In
previous studies, the Geyer laboratory has housed animals on a reverse
dark/light cycle and tested animals during the dark phase
(Henry et al., 2002). Thus, we
were additionally interested in testing the contribution of this variable to
the observation of significant deficits in these mice. Our mice were housed on
a reverse dark/light cycle, initially tested during their dark phase
(Fig. 4, studies 1 and 2), and
subsequently tested during their light phase
(Fig. 4, study 3). We found
significant and reproducible deficits in these animals regardless of testing
time within the dark/light cycle. Because previous reports have been
restricted to abstract publications, details that could account for
inconsistencies between these reports remain to be elucidated. One obvious
possibility is sample size. In the present study, we used relatively large
group sizes. In our present study, a group size of 12 to 13 resulted in
effects modest in magnitude (p values 0.04). In comparison, we
have replicated these results (data not shown) with a separate group of mice
where the group size was increased to 25 to 26 animals per group. In these
data, the difference between mGluR5 knockout and wild-type mice, although
similar in magnitude, is more statistically robust (i.e., p values
< 0.001).
Similar to the present studies using PCP, preliminary reports indicate that
MPEP also potentiates methamphetamine-induced hyperlocomotion and disruption
of PPI (Kinney et al., 2002).
Furthermore, we have presently demonstrated that CHPG can ameliorate the
disruptive effects of amphetamine on PPI. Collectively, these data suggest
that the mGluR5 system can modulate PPI and stimulant-induced locomotor
activity regardless of the stimulant used (i.e., PCP versus methamphetamine).
Thus, mGluR5/NMDAR interactions may not wholly account for the contribution of
mGluR5 in the behaviors measured herein. Group I mGlu receptors are known to
modulate dopamine release in the prefrontal cortex. Thus, the nonselective
group I agonist (+)-3-hydroxyphenylglycine has been shown to significantly
reverse PCP-induced dopamine release in the rat prefrontal cortex
(Maeda et al., 2003). Because
amphetamine similarly enhances dopamine release in the prefrontal cortex
(Moghaddam et al., 1990), it
remains possible that mGlu5 receptors are having the effects reported herein
via a dopamine-dependent mechanism independent from a primary effect on
NMDARs. Although mGluR5 localization is typically regarded as postsynaptic,
fiber labeling has also been described
(Hay et al., 1999), consistent
with known dopamine release sites on axonal varicosities
(Wong et al., 1999).
Furthermore, it has been demonstrated that enhancement of locomotor activity
in response to infusion of nonselective group I mGluR agonists into the
nucleus accumbens is dependent on intact dopaminergic neurotransmission
(Attarian and Amalric, 1997;
Meeker et al., 1998).
Collectively, these data could suggest that mGlu5 receptors modulate
amphetamine- and PCP-mediated activity via a direct interaction with
dopaminergic systems or, alternatively, neuronal circuitry commonly affected
by NMDA and dopaminergic mechanisms. The possibility that mGluR5 interacts
with NMDA and dopamine systems independently must also be considered, given
the lack of evidence to the contrary.
In summary, the results of the present manuscript demonstrate that PCP-induced behavior is augmented after coapplication of the mGluR5 antagonist MPEP. We further found that infusion of the mGluR5 agonist CHPG reverses the disruptive effects of amphetamine on PPI in rats and that mGluR5–/– mice demonstrate a consistent and reliable, albeit modest, deficit in PPI relative to their wild-type controls. Collectively, these data are consistent with a modulatory role for mGluR5 in preclinical behaviors sensitive to antipsychotic drug treatment and further support a potential therapeutic role for mGluR5 agonists/potentiators in the treatment of schizophrenia, psychosis, and related disorders.
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Footnotes |
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ABBREVIATIONS: NMDAR, N-methyl-D-aspartate receptor; PCP, phencyclidine; mGluR, metabotropic glutamate receptor; PPI, prepulse inhibition; MPEP, 2-methyl-6-(phenylethynyl)pyridine; CHPG, (R,S)-2-chloro-5-hydroxyphenylglicine; NMDA, N-methyl-D-aspartate; LY314582, racemic (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Address correspondence to: Dr. Gene G. Kinney, Department of Neuroscience, Merck and Co., Inc., P.O. Box 4, WP46–300, West Point, PA 19486. E-mail: gene_kinney{at}merck.com
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, significant difference from Veh + PCP (1 mg/kg s.c.) condition,
