mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition

Neuropharmacology 49 (2005) 73e85 www.elsevier.com/locate/neuropharm

mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition M. Pietraszeka,b, A. Graviusa, D. Scha¨fera, T. Weila, D. Trifanovac, W. Danysza,* a

Preclinical R&D, Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany b Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Cracow, Poland c 3 Latvian Institute of Organic Synthesis, Aizkraules 21, Riga, LV1006, Latvia Received 2 December 2004; received in revised form 25 January 2005; accepted 31 January 2005

Abstract Hypoglutamatergic theory of schizophrenia is substantiated by observation that high affinity uncompetitive antagonists of NMDA receptors such as PCP can induce psychotic symptoms in humans. Recently, metabotropic glutamate receptors of the mGluR5 type have also been discussed as possible players in this disease. However, less is known about the potential contribution of mGluR1 in schizophrenia. Therefore, the aim of the present study was to compare the effect of selective mGluR1 antagonist EMQMCM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist (MTEP ([(2-methyl-1, 3-thiazol-4-yl) ethynyl] pyridine) either alone or in combination with (C)MK-801 in a prepulse inhibition (PPI) model and locomotor activity tests. Additionally, the effect of both mGluR1 and mGluR5 antagonists on (C)MK-801-evoked ataxia was tested. In contrast to (C)MK-801, which induced disruption of PPI, neither MTEP (1.25e5 mg/kg) nor EMQMCM (0.5e4 mg/kg) altered the PPI. However, MTEP, but not EMQMCM, enhanced disruption of PPI induced by (C)MK-801. Although neither mGluR1 nor mGluR5 antagonists given alone changed locomotor activity of rats, MTEP at 5 mg/kg potentiated the effect of (C)MK-801 while EMQMCM (up to 4 mg/kg) turned out to be ineffective. On the other hand, EMQMCM, but not MTEP, enhanced ataxia evoked by MK-801. The present results demonstrate that blockade of mGluR1 and mGluR5 evokes different effects on behavior induced by NMDA receptor antagonists. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Group I mGluRs; NMDA receptors; Schizophrenia; Prepulse inhibition; Locomotor activity

1. Introduction Glutamate is a primary excitatory neurotransmitter in the brain, acting through two major classes of receptors: glutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) and G protein-coupled metabotropic glutamate receptors (mGluRs) (Parsons et al., 1998; Schoepp et al., 1999). The iGluRs include N-methyl-D-aspartate (NMDA), AMPA and kainate receptors (Parsons et al., 1998). Until now, eight mGluR * Corresponding author. Tel.: C49 69 150 35 64; fax: C49 69 596 21 50. E-mail address: [email protected] (W. Danysz). 0028-3908/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2005.01.027

subtypes (mGluR1e8) have been identified and classified into group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3) and group III mGluRs (mGluR4 and mGluR6-8) (Schoepp et al., 1999). During recent years, numerous studies have indicated that the function of the glutamatergic system, in particular NMDA receptors, might be disturbed in schizophrenia. Post-mortem studies have found abnormalities in the density of NMDA receptors and changes in expression and phosphorylation of their subunits mainly in the cerebral cortex and in the hippocampus of patients affected by schizophrenia (Ishimaru et al., 1992; Simpson et al., 1992; Dracheva et al., 2001; Emamian et al., 2004), for review see (Meador-Woodruff and Healy, 2000). It is

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also well documented that uncompetitive, high affinity antagonists of NMDA receptors such as phencyclidine can trigger both positive and negative symptoms in normal subjects and exacerbate psychotic symptoms in schizophrenia patients (Luby et al., 1959; Krystal et al., 1994). In contrast, agonists interacting at the glycine site of the NMDA receptor complex, e.g. glycine or D-serine, administered together with typical neuroleptics might alleviate symptoms of schizophrenia (Javitt et al., 1994; Tsai et al., 1998). In animals, administration of phencyclidine or (C)-5methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((C)MK-801), another uncompetitive NMDA receptor antagonist, leads to behavioral alterations that are supposed to correspond to some aspects of schizophrenia. Those alterations include disruption of sensorimotor gating, social interaction deficit, working memory impairment as well as enhanced locomotor activity of animals (Mansbach and Geyer, 1989; Danysz et al., 1994; Sams-Dodd, 1996; Moghaddam et al., 1997). However, less is known about the role of mGluRs in schizophrenia. Recent studies revealed an elevated level of mGluR5 mRNA in the prefrontal cortex of schizophrenics (Ohnuma et al., 1998) as well as an association of allele frequency of gene coding for mGluR5 with schizophrenia (Devon et al., 2001). Interestingly, group I mGluRs (mGluR1 and mGluR5) could be physically connected with NMDA receptors and their stimulation positively modulates the function of NMDA in several brain regions (Awad et al., 2000; Pisani et al., 2001; Attucci et al., 2001; Mannaioni et al., 2001; Lan et al., 2001; Heidinger et al., 2002; Benquet et al., 2002b). On the contrary, antagonists of mGluR5 augmented behavioral impairment, an indicator of psychotomimetic-like activity produced by uncompetitive NMDA receptor antagonists in animals (Henry et al., 2002; Kinney et al., 2003; Campbell et al., 2004; Homayoun et al., 2004). Deficit of prepulse inhibition of the acoustic startle (PPI, animal model of sensorimotor gating) has also been observed in mGluR1 knockout mice (Brody et al., 2003), suggesting that those receptors are involved in schizophrenia. However, so far, only a few studies have examined the effect of mGluR1 antagonists in animal models relevant for this disease such as stereotypy and PPI (De Vry et al., 2001; Lesage et al., 2002). The aim of the present study was to examine the role of mGluR1 and mGluR5 in animal models relevant for schizophrenia. For this purpose, the mGluR1 antagonist 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)methanone methanesulfonate (EMQMCM) (Lesage et al., 2002) and the mGluR5 antagonist [(2-methyl-1, 3-thiazol-4-yl) ethynyl] pyridine (MTEP) (Busse et al., 2004) were studied either alone or in combination with the uncompetitive NMDA receptor antagonist ((C)MK-801) in locomotor activity tests and the prepulse inhibition model. Additionally, the effect of both mGluR1 and

mGluR5 antagonists on (C)MK-801-evoked ataxia was investigated. The present results have been presented previously in abstract form (Pietraszek et al., 2004a).

2. Materials and methods 2.1. Animals The experiments were performed on male Spraguee Dawley rats (Janvier; Le Genest-Saint-Isle, France, 230e 300 g) were kept under standard laboratory conditions (four per cage) in a room with controlled temperature (21G1
C) and humidity. Food and water were available ad libitum and the animals were kept under an artificial light/dark cycle (12/12 h, light on 7 am). All experiments were performed between 9 am and 5 pm. The procedures were approved by the Ethical Committee, Regierungspraesidium Darmstadt, Hessen. 2.2. Drugs EMQMCM (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, synthesized by Merz Pharmaceuticals, Frankfurt, Germany) was dissolved in distilled water containing Tween 80 (10%) whereas MTEP ([(2-methyl-1, 3-thiazol-4-yl) ethynyl] pyridine synthesized by Merz Pharmaceuticals, Frankfurt, Germany) was dissolved in distilled water or in distilled water containing Tween 80 (10%). (C) MK-801 (Tocris Avonmouth, UK) was dissolved in physiological saline. All compounds were injected intraperitoneally (2e4 ml/kg). 2.3. Locomotor activity For testing locomotor activity, MTEP (2.5 or 5 mg/ kg), EMQMCM (1 or 4 mg/kg) or the vehicle were injected 10 min before (C)MK-801 (0.2 mg/kg) or its solvent (physiological saline). The test started 10 min after (C)MK-801 administration. Locomotor activity was measured in four Perspex boxes (43.2!43.2!30 cm) placed in noise-proof chambers equipped with a ventilator and a source of white light (5.6 W) which was placed 55 cm above the floor. For the measurement of the activity a Med-Associates Inc. system was applied. Four arrays of 16 infrared photo beams placed 3 cm above the floor measured horizontal activity. Activity was assessed as the mean distance traveled (cm). Box size was set to four (minimal photo beams interruption resulting in counts) which precluded counting of stereotypy. At least 1 h prior to testing, rats were acclimated to the testing room. The recording started immediately

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after placing animals in the open field and continued for 120 min in 20 min intervals.

2.4. Prepulse inhibition 2.4.1. Apparatus Four sound-proof startle chambers were used to measure the startle response (Med Associates). Each well-ventilated chamber contained acrylic animal holders (19 cm length and 7.6 cm width) placed on a piezoelectric force transducer connected to an analog-to-digital converter (Med Associates, Model PHM-250B). The startle-eliciting noise bursts were generated via a noise generator (Med Associates, Model PHM-255A) and additional speaker produced a background noise. Speakers were placed 7 cm apart from the animal holder in the back of the chamber. Overall background noise produced by ventilators and noise generator was 68 dB in total. The chambers were connected through an interface to an IBM-PC. All stimuli and each force transducer were calibrated prior to each test session.

2.4.2. Procedure In the PPI test all compounds tested alone (MTEP, EMQMCM, or (C)MK-801) were administered 30 min before the experiment started. Then, in a combination study, rats received MTEP (5 mg/kg), EMQMCM (4 mg/kg) or vehicle and 10 min later (C)MK-801 (0.1 or 0.2 mg/kg) or its solvent. The measurement started 50 min after (C)MK-801 administration. Two to three days before proper experiments, all animals were pretested in order to divide them into groups with comparable PPI and startle amplitude values. The experiment started with a 5 min adaptation period during which the animals were exposed to 68 dB background white noise and this background noise was continued throughout the session. Then, the following adaptation period startle session began with five initial startle stimuli (118 dB bursts of white noise, 40 ms duration) in order to partially habituate animals to the startle-eliciting stimulus (data was not taken for further calculations). After the first five initial stimuli, rats received five different trial types: pulse alone trials (118 dB bursts of white noise, 40 ms duration); three prepulse and pulse trials in which 72, 76 or 84 dB white noise bursts (4, 8 and 16 dB above background) of 20 ms duration, preceded 118 dB pulse by 100 ms (prepulse onset to pulse onset); and no-stimuli trials during which only background noise was applied. Each of these trial types was presented 12 times in randomized order. The intertrial interval was 7e23 s and the test lasted 22 min in total. Additionally, motor activity in restrainers was

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measured during the experiment and calculated as a mean of peaks from 12 trials which were measured as the maximum value recorded in 100 ms during no stimulus trials. In PPI experiments assessing the effect of (C)MK-801 and MTEP alone prepulse intensities of 69, 74 and 80 dB were used (3, 6 and 12 dB above background).

2.5. Rotarod test In the rotarod test, rats were pretreated with MTEP (5 mg/kg), EMQMCM (5 mg/kg) or the vehicle and, 5 min later, were given injection of 0.1 mg/kg (C)MK-801 or its solvent. The experiment started 25 min after (C)MK-801 administration. Before performing the test, animals were trained on the rotarod until they reached a stable performance in this test (w200 s on rotarod). In accordance with the training session, the test session comprised two trials. At least 1 h before the experiment, animals were brought to the experimental room. Then, all rats were placed on an accelerating rotarod apparatus (Ugo Basile Accelerating Rota-Rod ‘‘Jones & Roberts’’ for Rats 7750) with an initial speed of 4 rotations per minute (rpm). Thereafter, the speed gradually increased to 40 rpm over 300 s (regarded as a ‘‘cut-off’’ time).

2.6. Data analysis The locomotor activity data was analyzed using repeated two-way ANOVA. In case a significant effect was observed, it was followed by a Duncan’s test. Startle amplitude for each trial type presentation was calculated as a mean value of the peaks from 12 trials (the maximum value recorded in 100 ms beginning with the onset of startle stimulus). Prepulse inhibition was calculated as the percent inhibition of the startle amplitude evoked by the pulse alone: %PPIZ100! (magnitude on pulse alone trialmagnitude on prepulseCpulse trial/magnitude on pulse alone trial). The mean startle amplitudes gained from the pulse alone trials were analyzed via the one- or two-way ANOVA which was followeddif significantdby Duncan’s test. %PPI was analyzed using repeated two- or three-way ANOVAs (with pretreatment and treatment as between subject factors and prepulse intensity as within subject factor) followed by Duncan’s test, when appropriate. Motor activity was analyzed by one- or two-way ANOVA followeddif significantdby Duncan’s test. Data from the rotarod test was analyzed using a twoway ANOVA followeddif significantdby Duncan’s test.

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3. Results

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3.1.2. The effect of MTEP on (C)MK-801-induced locomotor activity Systemic administration of (C)MK-801 (0.2 mg/kg) enhanced the locomotor activity of animals (Fig. 2). Interestingly, MTEP (2.5 and 5 mg/kg) administered alone did not alter spontaneous locomotor activity of animals, however it dose-dependently potentiated (C)MK-801-induced locomotor activity (Fig. 2). The two-way RM ANOVA experiment revealed a significant effect of treatment [F(5,54)Z11.58, P!0.001], time [F(5,270)Z55.33, P!0.001] and treatment!time interaction [F(5,270)Z8.784, P!0.001], and the post hoc comparison indicated a significant difference between the vehicle and (C)MK-801 treated rats as well as between animals treated with MTEP (5 mg/kg) prior to (C)MK801 and those which received vehicle and additional (C)MK-801 injection (Fig. 2).

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Time (min) Fig. 1. Effect of EMQMCM on (C)MK-801-induced hyperlocomotion in rats. EMQMCM or its vehicle was injected 10 min before (C)MK801. Measurement started 10 min after (C)MK-801 administration. Results are expressed as meanGSEM. Number of animals in groups nZ11e12. Data were analyzed by two-way repeated measure of variance followed by Duncan’s test. *P!0.05 vs. vehicle/vehicle during the whole registration period.

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3.1.1. The effect of EMQMCM on (C)MK-801-induced locomotor activity An increase in the locomotor activity produced by (C)MK-801 (0.2 mg/kg) in rats was not affected by pretreatment with EMQMCM (1 and 4 mg/kg) (Fig. 1). The two-way RM ANOVA revealed a significant effect of treatment [F(5,65)Z17.91, P!0.001], time [F(5,325) Z53.23, P!0.001] and treatment!time interaction [F(5,325)Z5.65, P!0.001]. Duncan’s post hoc comparison revealed only a significant difference between the vehicle and (C)MK-801 treated animals (Fig. 1).

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Time (min) Fig. 2. Effect of MTEP on (C)MK-801-induced hyperlocomotion in rats. MTEP or its vehicle was injected 10 min before (C)MK-801. Measurement started 10 min after (C)MK-801 administration. Results are expressed as meanGSEM. Number of animals in groups nZ10. Data were analyzed by two-way repeated measure of variance followed by Duncan’s test. *P!0.05 vs. vehicle/vehicle, #P!0.05 vs. vehicle/ (C)MK-801 treatment during the whole registration period.

3.2. PPI test 3.2.1. The effect of (C)MK-801, EMQMC and MTEP administered alone A significant effect of (C)MK-801 treatment [F(3,36)Z9.32, P!0.001] extended by the post hoc analysis demonstrated that (C)MK-801 at 0.1, 0.15 and 0.2 mg/kg induced disruption of PPI (Fig. 3A). (C)MK801 had no significant effect on startle amplitude to pulse alone [F(3,36)Z2.4, NS] (Fig. 3B). Additionally, oneway ANOVA revealed a significant effect of (C)MK-801 on motor activity of animals as measured in the PPI apparatus [F(3,36)Z5.35, P!0.001] (Fig. 3C). The post hoc analysis demonstrated that the motor activity was increased at 0.15 and 0.2 mg/kg doses. In contrast to (C)MK-801, EMQMCM (0.5e4 mg/ kg) or MTEP (1.25e5 mg/kg) administered alone had no effect on PPI (Fig. 4A, 5A), startle amplitude to pulse alone (Fig. 4B, 5B) and did not alter motor activity of animals measured in PPI apparatus (Fig. 4C, 5C). 3.2.2. The effect of combined treatment with EMQMCM and (C)MK-801 (C)MK-801 (0.1 and 0.2 mg/kg) induced disruption of PPI which was not affected by the pretreatment with EMQMCM (4 mg/kg) (Fig. 6A). There was only a significant main effect of (C)MK-801 treatment [F(2,64)Z12.26, P!0.001] and post hoc comparison revealed a significant difference between the vehicle- and (C)MK-801 groups (Fig. 6A). Although there was a main effect of (C)MK-801 treatment on the startle amplitude evoked by pulse alone [F(2,64)Z4.07, P!0.05] and a significant pretreatment!treatment interaction [F(2,64)Z3.99, P!0.05], post hoc analysis showed only a significant difference

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Fig. 3. Effect of (C)MK-801 on PPI (A), startle amplitude (B) and motor activity measured in PPI apparatus (C). (C)MK-801 was administered 30 min before test. Results are expressed as meanGSEM. Number of animals in groups nZ10. Data were analyzed by two-way RM ANOVA (% PPI) or by one-way ANOVA (startle amplitude and motor activity) followed by Duncan’s test. *P!0.05 vs. vehicle.

between the vehicle plus vehicle and all other groups (Fig. 6B). A significant main effect of (C)MK-801 [F(2,64)Z11.62, P!0.001] and a post hoc comparison revealed that animals treated with (C)MK-801 (0.2 mg/ kg) were more active than those in the vehicle plus vehicle group (Fig. 6C). 3.2.3. The effect of combined treatment with MTEP and (C)MK-801 Fig. 7 displays the effect of combined treatment with MTEP (5 mg/kg) and (C)MK-801 (0.1 mg/kg) on PPI (Fig. 7A), startle amplitude to pulse alone (Fig. 7B) and motor activity of animals measured in the PPI apparatus (Fig. 7C). Analysis of PPI data indicated that there was a significant effect of (C)MK-801 treatment [F(1,35)Z 8.37, P!0.01], whereas post hoc analysis demonstrated only significant disruption of PPI in animals treated jointly with MTEP and (C)MK-801 in comparison to all other groups (Fig. 7A). The two-way ANOVA revealed a significant effect of (C)MK-801 treatment on startle amplitude

[F(1,35)Z5.28, P!0.05]. Post hoc analysis indicated a significant difference between vehicle plus vehicle and vehicle plus (C)MK-801 treated groups (Fig. 7B). MTEP neither affected startle amplitude in normal rats [F(1,35)Z0.08, NS] nor influenced the startle amplitude enhanced by (C)MK-801, pretreatment!treatment interaction [F(1,35)Z0.85, NS] (Fig. 7B). (C)MK-801 at a dose of 0.1 mg/kg alone and MTEP at a dose of 5 mg/kg alone did not alter motor activity of animals, however the combined administration of (C)MK-801 and MTEP increased motor activity of animals (Fig. 7C). There was significant main effect of (C)MK-801 treatment [F(1,35)Z22.11, P!0.001] and significant pretreatment!treatment interaction [F(1,35)Z7.26, P!0.05] (Fig. 7C). In another experiment (Fig. 8), the effect of the combined treatment with MTEP (5 mg/kg) and (C)MK801 (0.2 mg/kg) on PPI (8A), startle amplitude to pulse alone (Fig. 8B) and motor activity of animals were measured in PPI apparatus (Fig. 8C). (C)MK-801 (0.2 mg/kg) induced disruption of PPI and that effect was potentiated by MTEP (5 mg/kg) (Fig. 8A). There was

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Fig. 4. Effect of EMQMCM on PPI (A), startle amplitude to pulse alone (B) and motor activity measured in PPI apparatus (C). EMQMCM was administered 30 min before test. Results are expressed as meanGSEM. Number of animals in groups nZ10.

a significant main effect of (C)MK-801 treatment [F(1,39)Z59.5, P!0.001] and a significant pretreatment!treatment interaction [F(1,39)Z10.54, P!0.01]. Post hoc comparison revealed a significant difference between (C)MK-801 treated rats in comparison to all other groups and a significant difference between animals treated with MTEP (5 mg/kg) prior to (C)MK-801 and those which received vehicleC(C)MK-801 injection (Fig. 8A). A significant effect of (C)MK-801 treatment [F(1,39)Z7.19, P!0.05] extended by a post hoc analysis demonstrated that startle amplitude was increased in animals treated with vehicle plus (C)MK-801 in comparison to vehicle plus vehicle (Fig. 8B). MTEP neither affected the startle amplitude in normal rats [F(1,39)Z3.59, NS] nor influenced the startle amplitude enhanced by (C)MK-801, pretreatment!treatment interaction [F(1,39)Z0.83, NS] (Fig. 8B). The analysis of the motor activity data indicated that there was a significant effect of (C)MK-801 treatment [F(1,39)Z15.01, P!0.01] and MTEP pretreatment [F(1,39)Z4.04, P!0.05]. Here, post hoc analysis showed only a significant enhancement of the motor activity in

animals treated jointly with MTEP and (C)MK-801 in comparison to all other groups (Fig. 8C). 3.3. Rotarod test Fig. 9 shows the effect of EMQMCM (5 mg/kg) and (C)MK-801 (0.1 mg/kg) on the rotarod performance. Two-way ANOVA revealed a significant effect of pretreatment with EMQMCM [F(1,27)Z7.568, P! 0.01] and a significant effect of treatment with (C)MK801 [F(1,27)Z12.69, P!0.001]. However, Duncan’s post hoc analysis demonstrated only a significant motor impairment in animals treated jointly with EMQMCM (5 mg/kg) and (C)MK-801 (0.1 mg/kg) in comparison with all other groups (Fig. 9). MTEP (5 mg/kg) and (C)MK-801 (0.1 mg/kg), alone and in combination did not affect the performance of rats on rotarod apparatus (Fig. 10). 4. Discussion Several studies have revealed that high affinity uncompetitive NMDA receptor antagonists produce

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Fig. 5. Effect of MTEP on PPI (A), startle amplitude (B) and motor activity measured in PPI apparatus (C). MTEP was administered 30 min before test. Results are expressed as meanGSEM. Number of animals in groups nZ8e9.

psychotic symptoms in humans (Krystal et al., 1994), whereas their administration to animals induce deficit of PPI and increased locomotor activity (Mansbach and Geyer, 1989; Keith et al., 1991; Danysz et al., 1994; Bakshi et al., 1994). Interestingly, such behavioral impairment induced by uncompetitive NMDA receptor antagonists is potentiated by the mGluR5 antagonist MPEP (Henry et al., 2002; Kinney et al., 2003; Pietraszek et al., 2004b). In the present study, we have tested whether the more selective mGluR5 antagonist, MTEP (Anderson et al., 2003; Cosford et al., 2003a) and the mGluR1 antagonist, EMQMCM, might induce schizophrenia-like symptoms or potentiate such effects of NMDA receptor antagonists. EMQMCM is a noncompetitive mGluR1 antagonist with an IC50 value of about 3 nM (Lesage et al., 2002). At doses tested in the present experiments, EMQMCM induced anxiolytic effects in animal models of anxiety (Danysz et al., 2004). On the other hand, it has been demonstrated that MTEP is more selective in vitro and more potent in in vivo tests for anxiety than MPEP (Anderson et al., 2003; Cosford et al., 2003b; Busse et al., 2004). In agreement with several previous reports the present study also indicated that the uncompetitive NMDA receptor antagonist, (C)MK-801, enhanced locomotor

activity of rats and induced sensorimotor gating deficit as reflected by the reduction in PPI. However, neither mGluR5 (MTEP) nor mGluR1 (EMQMCM) antagonist induced behavioral alterations similar to those provoked by uncompetitive NMDA receptor antagonists. In contrast to (C)MK-801, mGluR antagonists that were applied herein did not enhance locomotion of animals at the doses used, and in fact, at higher doses both MTEP (10 mg/kg) and EMQMCM (10 mg /kg) slightly diminished spontaneous locomotor activity (data not shown). Moreover, disruption of PPI have been previously reported in mice lacking mGluR1 or mGluR5 (KO) (Kinney et al., 2003; Brody et al., 2003; Brody and Geyer, 2004), but not in animals treated with antagonists of those receptors (De Vry et al., 2001; Henry et al., 2002; Kinney et al., 2003). Our current study supports the latter observations showing that neither MTEP nor EMQMCM induce sensorimotor gating deficit in rats. Therefore, it is possible that the reduction in PPI observed in mGluR1 or mGluR5 knock out mice might be due to compensatory changes that occur during the development. Although, MTEP did not alter spontaneous locomotor activity and did not disrupt PPI on its own, it augmented such effects produced by (C)MK-801.

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Fig. 6. The effect of combined treatment with EMQMCM (4 mg/kg) and (C)MK-801 (0.2 mg/kg) on PPI (A), startle amplitude (B) and motor activity measured in PPI apparatus (C). EMQMCM or its vehicle was injected 10 min before (C)MK-801. Measurement started 50 min after (C)MK-801 administration. Results are expressed as meanGSEM. Number of animals in groups nZ11e12. Data were analyzed by three-way RM ANOVA (% PPI) and or two-way ANOVA (startle amplitude and motor activity) followed by Duncan test. *P!0.05 vs. vehicle/vehicle.

Combined treatment with MTEP and low dose of (C)MK-801 (0.1 mg/kg) induced disruption of PPI and enhanced motor activity measured in the PPI apparatus. Moreover, MTEP potentiated the disruption of PPI and extended locomotor activity evoked by (C)MK-801 given at a dose of 0.2 mg/kg. In contrast to MTEP, mGluR1 antagonists, EMQMCM did not alter the deficit of PPI or locomotor activity elicited by (C)MK-801. Thus, mGluR1 and mGluR5 antagonists may induce different effects on behavioral alterations evoked by uncompetitive NMDA receptor antagonists. In fact, the consequence of higher doses of EMQMCM on the (C)MK-801-induced effect was not examined. However, as has been mentioned above, at doses tested in the present study, EMQMCM induced an anxiolytic effect in animal models of anxiety (Danysz et al., 2004). Moreover, although EMQMCM at least up to a dose of 5 mg/kg did not induce motor coordination deficit (ataxia) on its own, it potentiated such effects evoked by (C)MK-801. In contrast, MTEP did not affect (C)MK801-induced ataxia, giving additional evidence for a different regulation of NMDA receptors by mGluR1 and mGluR5 antagonists. This might be explained by

the fact that mGluR1s are highly expressed in the cerebellum, a brain structure responsible for motor coordination, whereas mGluR5s are almost absent there (Ichise et al., 2000; Lavreysen et al., 2004). The present results are consistent with previous publications showing that also another mGluR5 antagonist, MPEP, but not mGluR1 antagonist, BAY 367620, potentiates locomotor activity and disruption of PPI induced by (C)MK-801 or phencyclidine in rats (De Vry et al., 2001; Henry et al., 2002; Kinney et al., 2003). However, one earlier study presented in an abstract form demonstrated that EMQMCM derivative reversed ketamine-induced deficit of PPI (Lesage et al., 2002). The reason for such discrepancy is not clear and further studies will be essential to clarify differences between various mGluR1 and NMDA antagonists on PPI. For example, some studies have revealed a different effect of typical neuroleptics (e.g. haloperidol or raclopride) on the deficit of PPI evoked by phencyclidine and (C)MK801 vs ketamine in rats. Whereas acute treatment with typical neuroleptics fails to reverse the deficit of PPI evoked by (C)MK-801 or phencyclidine (Keith et al., 1991; Hoffman et al., 1993; Bakshi et al., 1994), at least

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Fig. 7. The effect of combined treatment with MTEP (5 mg/kg) and (C)MK-801 (0.1 mg/kg) on PPI (A), startle amplitude (B) and motor activity measured in PPI apparatus (C). MTEP or its vehicle was injected 10 min before (C)MK-801. Measurement started 50 min after (C)MK-801 administration. Results are expressed as meanGSEM. Number of animals in groups nZ9e10. Data were analyzed by three-way RM ANOVA (% PPI) and by two-way ANOVA (startle amplitude and motor activity) followed by Duncan’s test. *P!0.05 vs. vehicle/vehicle, xP!0.05 vs all other groups.

some studies have shown that such a deficit produced by ketamine is diminished by haloperidol or chlorpromazine (Swerdlow et al., 1998; Mansbach et al., 2001). In general, locomotor activity is associated with ventral striatum function, whereas prefrontal cortex, hippocampus and amygdala have been suggested to play an important role in PPI-disruptive effects of NMDA receptor antagonists (Willins et al., 1993; Bakshi and Geyer, 1998; Schwabe and Koch, 2004). Both mGluR1 and mGluR5 are present in all of those brain structures (Kerner et al., 1997; Lavreysen et al., 2004; for review see Spooren et al., 2003). However, it has been found previously that mGluR1 and mGluR5 exhibit a distinct localization in the striatum, cerebral cortex and hippocampus, which suggests that those receptors might have a different role in the central nervous system (Shigemoto et al., 1997; Kerner et al., 1997). Indeed, several but not all in vitro studies have revealed a distinct function of mGluR1 and mGluR5 (Awad et al., 2000; Mannaioni et al., 2001; Poisik et al., 2003; Gubellini et al., 2003; Rae and Irving, 2004; for review see Valenti et al., 2002). Moreover, in spite of the fact that both mGluR1 and

mGluR5 can be physically and functionally connected with NMDA receptors, their effect on NMDA receptor function might vary between brain structures (Tu et al., 1999; Awad et al., 2000; Attucci et al., 2001; Mannaioni et al., 2001; Heidinger et al., 2002). For example, in the CA1 regions of the hippocampus stimulation of mGluR5, but not mGluR1, potentiates NMDA-evoked currents (Doherty et al., 1997; Mannaioni et al., 2001). Consistent with these observations, the function of NMDA receptors as well as NMDA-dependent LTP in mGluR5 knock-out mice is reduced in this brain region (Lu et al., 1997; Jia et al., 1998). Functional segregation between mGluR1 and mGluR5 has also been found in various basal ganglia structures (Awad et al., 2000; Pisani et al., 2001; Marino et al., 2001) and in the cerebral cortex (Attucci et al., 2001; Heidinger et al., 2002), although in this latter structure conflicting results have been presented. Moreover, in the CA3 region of the hippocampus stimulation of both mGluR1 and mGluR5 enhances NMDA receptor function (Benquet et al., 2002). However, the intracellular mechanisms responsible for this effect differs (Benquet et al., 2002) since mGluR5 potentiates NMDA-evoked current via

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Fig. 8. The effect of combined treatment with MTEP (5 mg/kg) and (C)MK-801 (0.2 mg/kg) on PPI (A), startle amplitude (B) and motor activity measured in PPI apparatus (C). MTEP or its vehicle was injected 10 min before (C)MK-801. Measurement started 50 min after (C)MK-801 administration. Results are expressed as meanGSEM. Number of animals in groups nZ9e12. Data were analyzed by thee-way RM ANOVA (% PPI) and by two-way ANOVA (startle amplitude and motor activity) followed by Duncan’s test. *P!0.05 vs. vehicle/vehicle, #P!0.05 vs. vehicle/(C)MK-801. xP ! 0.05 vs. all other groups.

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a G protein activation, whereas mGluR1 enhances NMDA function via a G protein-independent mechanism involving Src tyrosine kinase activation (Benquet et al., 2002). The present study demonstrated that mGluR1 and mGluR5 might also differently regulate NMDA receptor function in vivo. The fact that mGluR5, but not mGluR1 antagonists augmented (C)MK-801induced locomotor activity and deficit of PPI might suggest that mGluR5 and NMDA receptors interact in controlling locomotion and PPI. It has also been demonstrated that uncompetitive NMDA receptor antagonists enhance dopamine, glutamate, norepinephrine and serotonin release, whereas inhibiting GABA efflux in the cerebral cortex and limbic structures (Wedzony et al., 1994; Yonezawa et al., 1998; Martin et al., 1998; Moghaddam and Adams, 1998; Sitges et al., 2000; Swanson and Schoepp, 2003). Compounds acting on those neurotransmitter systems modulate locomotor activity and/or PPI altered by uncompetitive NMDA receptor antagonists (Jackson et al., 1994; Maurel-Remy et al., 1995; Swerdlow et al., 1996; Moghaddam and Adams, 1998; Varty et al., 1999;

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M. Pietraszek et al. / Neuropharmacology 49 (2005) 73e85

References

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Fig. 10. Effect of MTEP (5 mg/kg, nZ8), (C)MK-801 (0.1 mg/kg, nZ8) and MTEPC(C)MK-801 (nZ8) on rotarod performance. Measurement started 30 min after MTEP and 25 min after (C)MK801 administration. Results are expressed as meanGSEM. Data were analyzed by two-way ANOVA followed by Duncan’s test.

Bakshi and Geyer, 1999; Swanson and Schoepp, 2003). For instance, the deficit of PPI produced by (C)MK-801 seems to be independent from its action on dopaminergic transmission (Keith et al., 1991; Hoffman et al., 1993; Bakshi et al., 1994; see above). However, locomotor activity elicited by this compound might, at least partially, be mediated via the enhancement of dopaminergic transmission, since this behavioral effect is inhibited by dopamine receptor antagonists (Hoffman, 1992; Jackson et al., 1994). Likewise, agonists of group II mGluRs, most likely via decreasing glutamate release, inhibit, whereas antagonists potentiate locomotion induced by uncompetitive NMDA receptor antagonists ((Moghaddam and Adams, 1998; Olszewski et al., 2004). Group I mGluRs might also regulate dopamine, glutamate and GABA release in cortical and subcortical structures (Bruton et al., 1999; Thomas et al., 2000; Battaglia et al., 2001; Swanson et al., 2001; Golembiowska et al., 2003; Homayoun et al., 2004). However, it is currently unknown whether different effects of mGluR1 and mGluR5 antagonists on (C)MK-801-induced behavior is related to diverse interactions with the above mentioned neurotransmitter systems. In conclusion, the present study suggests that antagonists of both mGluR1 and mGluR5 are devoid of psychotomimetic-like activity. However, the blockade of mGluR5, but not of mGluR1, might potentiate psychotic symptoms evoked by NMDA receptor antagonists whereas the combination of mGluR1 and NMDA receptor antagonists might induce motor coordination impairment. Thus, a different physiological function of mGluR1 and mGluR5 is emphasized by the present data.

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