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Andrzej Pilc - One of the best experts on this subject based on the ideXlab platform.
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activation of the mtor signaling pathway in the antidepressant like activity of the mglu5 antagonist MTEP and the mglu7 agonist amn082 in the fst in rats
Neuropharmacology, 2014Co-Authors: Agnieszka Paluchaponiewiera, Bernadeta Szewczyk, Andrzej PilcAbstract:Clinical studies have demonstrated rapid and long-lasting antidepressant effects of ketamine in depressive patients. It has been proposed that these effects are related to changes in synaptogenesis in the mechanism involving mammalian target of rapamycin (mTOR) activation. Similar mechanisms have been proposed for a group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. We aimed to investigate whether other mGlu receptor ligands that produce antidepressant-like effects, namely, the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082, induce the activation of mTOR signaling in the prefrontal cortex (PFC) in rats. AMN082 administered 60 min before the test increased the levels of pmTOR and pp70S6K, and the mTORC1 antagonist rapamycin reversed AMN082-induced changes in the forced swim test (FST) in rats. Furthermore, AMN082 administered 23 h before the decapitation of the rats increased the levels of synapsin I and GluR1, although it did not produce any effect in the FST at the same time point. However, MTEP induced a rapid but unsustained antidepressant-like effect, which was not related to the activation of the mTOR cascade. Finally, the antidepressant-like effects of MTEP or AMN082 were not antagonized by NBQX. In summary, the antidepressant-like activity of MTEP did not depend on the activation of mTOR signaling. However, we observed a unique feature of the mechanism of AMN082. The drug stimulated the mTOR signaling pathway and synaptic protein levels (like ketamine), while it did not induce a sustained antidepressant effect and its action was not directly dependent on AMPA receptor activation (as in classic antidepressants (ADs)).
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the antidepressant like action of mglu5 receptor antagonist MTEP in the tail suspension test in mice is serotonin dependent
Psychopharmacology, 2014Co-Authors: Agnieszka Paluchaponiewiera, Andrzej Pilc, Katarzyna Stachowicz, Piotr Branski, Joanna M Wieronska, Anna SlawinskaAbstract:Rationale Numerous studies indicate the potential antidepressant actions of several mGlu5 receptor antagonists, including 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP). The explanation for the mechanism of these effects might be a key step in finding new antidepressant drugs (AD).
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nmda but not ampa glutamatergic receptors are involved in the antidepressant like activity of MTEP during the forced swim test in mice
Pharmacological Reports, 2010Co-Authors: Lucyna Pomiernychamiolo, Gabriel Nowak, Andrzej Pilc, Ewa PoleszakAbstract:Abstract Several lines of evidence suggest an antidepressant-like activity for 3-[(methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), a highly selective, non-competitive antagonist of metabotropic glutamate receptors subtype 5 (mGluR 5 ). This effect has been observed following both acute and chronic MTEP treatments in behavioral tests and experimental models of depression, such as the forced swim test (FST), the tail suspension test, and the olfactory bulbectomy model of depression. However, the mechanism of action for mGluR 5 antagonists remains unclear. The aim of this study was to investigate whether the antidepressant-like action of MTEP is dependent on ionotropic glutamatergic receptors. Male Albino Swiss mice were used, and antidepressant-like activity was evaluated using the FST. The antidepressant-like effect of MTEP (0.3 mg/kg) was significantly antagonized by pre-treatment with the NMDA receptor agonist N-methyl-D-aspartic acid (NMDA, 75 mg/kg, ip ). The AMPA receptor antagonist NBQX (10 mg/kg, ip ) did not affect the MTEP activity. Our results indicate that the antidepressant-like activity of MTEP in the FST involves NMDA but not AMPA receptors and suggest that the interaction between mGluR 5 and NMDA receptors plays an important role in the underlying antidepressant mechanism(s).
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anxiolytic like action of MTEP expressed in the conflict drinking vogel test in rats is serotonin dependent
Neuropharmacology, 2007Co-Authors: Katarzyna Stachowicz, Gabriel Nowak, Andrzej Pilc, Krystyna Golembiowska, Magdalena Sowa, E ChojnackawojcikAbstract:Abstract The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.
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MTEP a new selective antagonist of the metabotropic glutamate receptor subtype 5 mglur5 produces antiparkinsonian like effects in rats
Neuropharmacology, 2005Co-Authors: K Ossowska, J Konieczny, S Wolfarth, Andrzej PilcAbstract:The aim of the present study was to examine a potential antiparkinsonian-like action of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), a new non-competitive antagonist of mGluR5, in the rat models. This compound has affinity for mGluR5 in a nanomolar concentration range and seems to be superior to the earlier known antagonists in terms of its specificity and bioavailability. Catalepsy and muscle rigidity induced by haloperidol administered at doses of 0.5 and 1 mg/kg were regarded as models of parkinsonian akinesia and muscle rigidity, respectively. MTEP at doses between 0.5 and 3 mg/kg i.p. decreased the haloperidol-induced muscle rigidity measured as an increased muscle resistance of the rat's hind leg in response to passive extension and flexion at the ankle joint. The strongest and the longest effect was observed after the dose of 1 mg/kg. MTEP (0.5-3 mg/kg i.p.) also reduced the haloperidol-induced increase in electromyographic (EMG) activity recorded in the gastrocnemius and tibialis anterior muscles. MTEP (3 and 5 mg/kg i.p.) inhibited the catalepsy induced by haloperidol. The present study confirms earlier suggestions that the antagonists of mGluR5 may possess antiparkinsonian properties. However, selective mGluR5 antagonists may be more effective in inhibiting parkinsonian muscle rigidity than parkinsonian akinesia.
Katarzyna Stachowicz - One of the best experts on this subject based on the ideXlab platform.
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behavioral consequences of co administration of MTEP and the cox 2 inhibitor ns398 in mice part 2
Neuroscience Letters, 2021Co-Authors: Katarzyna Stachowicz, Magdalena Sowakucma, P Panczyszyntrzewik, Paulina Misztak, Marcin Marciniak, Bartosz Bobula, K TokarskiAbstract:Our earlier study demonstrated, that antidepressant-like and also cognitive action of MTEP, a metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, was influenced by cyclooxygenase-2 (COX-2) inhibition in mice. We detected a decrease in the mGluR7 protein level in the hippocampus (HC) of mice co-treated chronically with MTEP and NS398 (a COX-2 inhibitor). We found both antidepressant-like effects and cognitive to be associated with mGlu7 receptor-mediated mechanisms.
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indomethacin a nonselective cyclooxygenase inhibitor does not interact with MTEP in antidepressant like activity as opposed to imipramine in cd 1 mice
European Journal of Pharmacology, 2020Co-Authors: Katarzyna StachowiczAbstract:Abstract The contribution of metabotropic glutamate receptors (mGlu receptors) in depression is well known and tested worldwide. Our previous study showed the involvement of the cyclooxygenase-2 (COX-2) pathway in behavioral changes mediated by an antagonist of metabotropic glutamate receptor subtype 5 (mGlu5 receptor) 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP). Among others, we have found that chronic concomitant administration of a COX-2 inhibitor and sub-effective dose of MTEP accelerates antidepressant-like activity of MTEP. This paper seeks to explore whether the same effect would be observed with the use of a non-selective COX inhibitor 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid (indomethacin). To that end, we have employed experimental procedure implemented in the earlier research. MTEP and indomethacin or MTEP + indomethacin were used chronically for 7 or 14 days. Then, the Porsolt test, tail suspension test and locomotor activity test were performed. Imipramine was used as a reference compound, as its action is connected with mGlu5 receptor. We found that, in contrast to COX-2 inhibition, indomethacin – acting both through COX-1 and COX-2 – did not release antidepressant-like potential of MTEP. The opposite effect was shown when imipramine was used.
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behavioral consequences of co administration of MTEP and the cox 2 inhibitor ns398 in mice part 1
Behavioural Brain Research, 2019Co-Authors: Katarzyna StachowiczAbstract:Abstract Background The immunologic modulation of glutamate (Glu) neurotransmission is a topic of great interest. Neuroinflammation is an intrinsic component of neurodegenerative diseases, as well as a factor responsible for cognitive and behavioral changes. Cyclooxygenase-2 (COX-2) expression in the brain was shown to be associated with inflammation. COX-2 is also widely expressed in the brain including neurons and glia and participates in fundamental brain functions, e.g. in synaptic plasticity or memory consolidation. Furthermore, COX-2/Glu interplay has been reported, while metabotropic glutamate receptors (mGluRs) are known to contribute to plastic changes and to behavior. The primary goal of this study was to explain the behavioral consequences of the modulation of the glutamatergic pathway via the interaction of the mGlu5 receptor and COX-2, utilizing a panel of behavioral tests. Methods To determine whether the glutamatergic pathway and COX-2 are involved in modulating the behavior of mice, C57B1/6 J and CD-1 male mice were injected daily with MTEP an mGluR5 antagonist, or a combination of MTEP and NS398 (COX-2 inhibitor) for 7 and 14 days. The following behavioral tests were used to screen for possible effects of the drug administration and interaction of the 2 compounds: the modified Barnes maze (MBM), stress-induced hyperthermia (SIH), Porsolt test (PT), tail suspension test (TST), modified rotarod (MR), and social interaction (SI) test. Results A time-dependent influence on spatial learning was found after the co-administration of MTEP and NS398. Furthermore, NS398 injected chronically amplified the antidepressant-like effects of MTEP in the PT and TST, and influenced the tolerance development observed after MTEP treatment in the SIH test.
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the antidepressant like action of mglu5 receptor antagonist MTEP in the tail suspension test in mice is serotonin dependent
Psychopharmacology, 2014Co-Authors: Agnieszka Paluchaponiewiera, Andrzej Pilc, Katarzyna Stachowicz, Piotr Branski, Joanna M Wieronska, Anna SlawinskaAbstract:Rationale Numerous studies indicate the potential antidepressant actions of several mGlu5 receptor antagonists, including 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP). The explanation for the mechanism of these effects might be a key step in finding new antidepressant drugs (AD).
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anxiolytic like action of MTEP expressed in the conflict drinking vogel test in rats is serotonin dependent
Neuropharmacology, 2007Co-Authors: Katarzyna Stachowicz, Gabriel Nowak, Andrzej Pilc, Krystyna Golembiowska, Magdalena Sowa, E ChojnackawojcikAbstract:Abstract The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.
Nicholas Dp Cosford - One of the best experts on this subject based on the ideXlab platform.
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The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety
Neuropsychopharmacology, 2004Co-Authors: Chris S Busse, Jesse Brodkin, Mark A Varney, Jeffery J Anderson, David Tattersall, Noelle Warren, Lida Tehrani, Linda J Bristow, Nicholas Dp CosfordAbstract:Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller–Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.
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Anxiolytic-like effects of MTEP, a potent and selective mGlu5 receptor agonist does not involve GABAA signaling
Neuropharmacology, 2004Co-Authors: Aleksandra Kłodzińska, Ewa Chojnacka-wójcik, Gabriel Nowak, Ewa Tatarczyńska, Nicholas Dp Cosford, Andrzej PilcAbstract:Abstract Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic drugs including the involvement of group I metabotropic glutamate (mGlu) receptors. Given the recent discovery of a selective and brain penetrable mGlu5 receptor antagonists, the effect of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), i.e. the most potent mGlu5 antagonist, was evaluated in established models of anxiety after single or repeated administration. We also studied if the anxiolytic effect of MTEP is mediated by mechanism involving the GABA–benzodiazepine (BZD) receptor complex. Experiments were performed on male Wistar rats or male Albino Swiss mice. The anxiolytic-like effects of MTEP were tested in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. MTEP (0.3–3.0 mg/kg) induced anxiolytic-like effects in the conflict drinking test (after single and repeated administration) and in the elevated plus-maze test in rats. In the four-plate test in mice, it exerted anxiolytic activity at a dose of 20 mg/kg. MTEP had no effect on the locomotor activity of animals. The anxiolytic-like effect of MTEP was not changed by BZD antagonist flumazenil. Moreover, a synergistic interaction between non-effective doses of MTEP and diazepam was observed in the conflict drinking test. These data suggest that selective mGlu5 receptor antagonists mediated anxiolysis is not dependent on GABA-ergic system and that these agents may play a role in the therapy of anxiety.
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3h methoxymethyl MTEP and 3h methoxy pepy potent and selective radioligands for the metabotropic glutamate subtype 5 mglu5 receptor
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Nicholas Dp Cosford, Lida Tehrani, Jeffrey Roger Roppe, Edwin J Schweiger, Jon T Seiders, Ashok Chaudary, Mark A VarneyAbstract:The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.
Andrew J Lawrence - One of the best experts on this subject based on the ideXlab platform.
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the effect of the mglu5 negative allosteric modulator MTEP and nmda receptor partial agonist d cycloserine on pavlovian conditioned fear
The International Journal of Neuropsychopharmacology, 2014Co-Authors: Andrew J Lawrence, Charlotte E Handford, Shawn Zheng Kai Tan, Jee Hyun KimAbstract:The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.
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the mglu5 receptor antagonist MTEP attenuates opiate self administration and cue induced opiate seeking behaviour in mice
Drug and Alcohol Dependence, 2012Co-Authors: Robyn M Brown, Monique R Stagnitti, Jhodie R Duncan, Andrew J LawrenceAbstract:The mGlu5 receptor (mGluR5) has been implicated in the rewarding effect of various drugs of abuse and drug-seeking behaviour. In the present study we investigated the impact of antagonism of mGluR5 with the selective negative allosteric, modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on operant self-administration of morphine as well as cue-induced drug-seeking in adult CD1 mice. Administration of MTEP (20 mg/kg, i.p.) attenuated operant responding for morphine (0.1 mg/kg/infusion) and cue-induced morphine-seeking after a period of forced abstinence. Collectively, these data implicate mGluR5 in the reinforcing effects of opiates and support the proposition that mGluR5 is a potential therapeutic target for treatment of drug addiction.
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the metabotropic glutamate 5 receptor antagonist 3 2 methyl 1 3 thiazol 4 yl ethynyl pyridine reduces ethanol self administration in multiple strains of alcohol preferring rats and regulates olfactory glutamatergic systems
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Michael S Cowen, Elvan Djouma, Andrew J LawrenceAbstract:The metabotropic glutamate 5 receptor (mGlu5) receptor has been implicated as having a role in pain modulation, anxiety, and depression, as well as drug-seeking behavior. In the present study, we examined the effect of the selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on operant ethanol self-administration by two strains of rats, the Fawn-Hooded (FH) rat and the inbred alcohol-preferring (iP) rat. MTEP (2 mg/kg i.p.) caused a significant reduction in responding for ethanol by both strains of rats; however, in the iP rats, MTEP also induced apparent sedation at this dose, although still reduced alcohol responding at lower doses. Chronic MTEP (2 mg/kg/day) caused a significant reduction in ethanol consumption by FH rats in a two-bottle preference test; however, chronic treatment with this dose had no effect on anxiety-like behavior or depressive-like behavior in FH rats, suggesting the dose used was subthreshold for anxiolytic or antidepressive-like effects. Finally, repeated dosing with MTEP (2 mg/kg i.p.) caused significant reductions in expression of the mRNA encoding the NR1 subunit of the N -methyl-d-aspartate receptor and the GluR2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor in the cingulate cortex. A significant decrease in NR1 expression also occurred in the piriform cortex. Chronic MTEP also caused a significant decrease in mGlu5 gene expression and a significant increase in dopamine transporter and dopamine D 2 -like receptor binding within the olfactory tubercle. Collectively, these data suggest that MTEP can reduce alcohol-seeking behavior in different rodent models of alcoholism, and this effect is associated with regulation of cortical glutamate systems, particularly those in olfactory-related regions.
Mark A Varney - One of the best experts on this subject based on the ideXlab platform.
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The Behavioral Profile of the Potent and Selective mGlu5 Receptor Antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in Rodent Models of Anxiety
Neuropsychopharmacology, 2004Co-Authors: Chris S Busse, Jesse Brodkin, Mark A Varney, Jeffery J Anderson, David Tattersall, Noelle Warren, Lida Tehrani, Linda J Bristow, Nicholas Dp CosfordAbstract:Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller–Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.
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3h methoxymethyl MTEP and 3h methoxy pepy potent and selective radioligands for the metabotropic glutamate subtype 5 mglu5 receptor
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Nicholas Dp Cosford, Lida Tehrani, Jeffrey Roger Roppe, Edwin J Schweiger, Jon T Seiders, Ashok Chaudary, Mark A VarneyAbstract:The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.
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anxiolytic like activity of the mglur5 antagonist mpep a comparison with diazepam and buspirone
Pharmacology Biochemistry and Behavior, 2002Co-Authors: Jesse Brodkin, Chris Busse, Stacey J Sukoff, Mark A VarneyAbstract:The selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)pyridine (MPEP) was shown to display anxiolytic-like activity in a number of unconditioned assays of stress and anxiety (elevated plus maze, shock probe burying, marble burying, social interaction, and stress-induced hyperthermia) in rodents. In this report, we extend these observations found using unconditioned models of anxiety to include three models of conditioned anxiety, comparing the activity of MPEP to the clinically used anxiolytics, diazepam, and buspirone. MPEP and diazepam, but not buspirone, showed anxiolytic-like activity in the fear-potentiated startle (FPS) model. In a conditioned ultrasonic vocalization (USV) procedure, MPEP, diazepam, and buspirone reduced vocalizations to a similar degree. In the modified Geller-Seifter procedure, MPEP, diazepam, and buspirone displayed statistically significant anxiolytic-like activity, increasing the number of punished responses. Thus, these findings confirm and extend previous reports that MPEP exhibits anxiolytic-like activity in rats, and suggests that development of mGluR5 antagonists may provide a novel approach to treating anxiety disorders.