The antipsychotic‐like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents

Background and Purpose Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain‐penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in sev...

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Veröffentlicht in:British journal of pharmacology 2013-08, Vol.169 (8), p.1824-1839
Hauptverfasser: Sławińska, Anna, Wierońska, Joanna M, Stachowicz, Katarzyna, Marciniak, Marcin, Łasoń‐Tyburkiewicz, Magdalena, Gruca, Piotr, Papp, Mariusz, Kusek, Magdalena, Tokarski, Krzysztof, Doller, Darío, Pilc, Andrzej
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container_issue 8
container_start_page 1824
container_title British journal of pharmacology
container_volume 169
creator Sławińska, Anna
Wierońska, Joanna M
Stachowicz, Katarzyna
Marciniak, Marcin
Łasoń‐Tyburkiewicz, Magdalena
Gruca, Piotr
Papp, Mariusz
Kusek, Magdalena
Tokarski, Krzysztof
Doller, Darío
Pilc, Andrzej
description Background and Purpose Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain‐penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents. Experimental Approach Hyperactivity induced by MK‐801 or amphetamine and head twitches induced by 2,5‐dimethoxy‐4‐iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK‐801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively. Key Results Lu AF21934 (0.1–5 mg·kg−1) and Lu AF32615 (2–10 mg·kg−1) dose‐dependently inhibited hyperactivity induced by MK‐801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4−/−) mice, Lu AF21934 did not antagonize DOI‐induced head twitches. MK‐801‐induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg−1 and by Lu AF32615 at 10 mg·kg−1. In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg−1, while Lu AF32615 was active at 10 mg·kg−1. Conclusions and Implications We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.
doi_str_mv 10.1111/bph.12254
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Experimental Approach Hyperactivity induced by MK‐801 or amphetamine and head twitches induced by 2,5‐dimethoxy‐4‐iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK‐801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively. Key Results Lu AF21934 (0.1–5 mg·kg−1) and Lu AF32615 (2–10 mg·kg−1) dose‐dependently inhibited hyperactivity induced by MK‐801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4−/−) mice, Lu AF21934 did not antagonize DOI‐induced head twitches. MK‐801‐induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg−1 and by Lu AF32615 at 10 mg·kg−1. In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg−1, while Lu AF32615 was active at 10 mg·kg−1. Conclusions and Implications We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/bph.12254</identifier><identifier>PMID: 23714045</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Allosteric Regulation ; Amphetamine ; Anilides - pharmacology ; Animals ; Antipsychotic Agents - pharmacology ; Cyclohexanecarboxylic Acids - pharmacology ; Disease Models, Animal ; Dizocilpine Maleate ; Dose-Response Relationship, Drug ; Excitatory Postsynaptic Potentials - drug effects ; Hyperkinesis - drug therapy ; Lu AF21934 ; Lu AF32615 ; Male ; mGlu receptors ; Mice ; Motor Activity - drug effects ; positive allosteric modulation ; Rats ; Receptors, Metabotropic Glutamate - drug effects ; Research Papers ; schizophrenia ; Schizophrenia - chemically induced ; Schizophrenia - drug therapy</subject><ispartof>British journal of pharmacology, 2013-08, Vol.169 (8), p.1824-1839</ispartof><rights>2013 The British Pharmacological Society</rights><rights>2013 The British Pharmacological Society.</rights><rights>British Journal of Pharmacology © 2013 The British Pharmacological Society</rights><rights>British Journal of Pharmacology © 2013 The British Pharmacological Society 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753838/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753838/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,1418,1434,27929,27930,45579,45580,46414,46838,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23714045$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sławińska, Anna</creatorcontrib><creatorcontrib>Wierońska, Joanna M</creatorcontrib><creatorcontrib>Stachowicz, Katarzyna</creatorcontrib><creatorcontrib>Marciniak, Marcin</creatorcontrib><creatorcontrib>Łasoń‐Tyburkiewicz, Magdalena</creatorcontrib><creatorcontrib>Gruca, Piotr</creatorcontrib><creatorcontrib>Papp, Mariusz</creatorcontrib><creatorcontrib>Kusek, Magdalena</creatorcontrib><creatorcontrib>Tokarski, Krzysztof</creatorcontrib><creatorcontrib>Doller, Darío</creatorcontrib><creatorcontrib>Pilc, Andrzej</creatorcontrib><title>The antipsychotic‐like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Background and Purpose Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain‐penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents. Experimental Approach Hyperactivity induced by MK‐801 or amphetamine and head twitches induced by 2,5‐dimethoxy‐4‐iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK‐801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively. Key Results Lu AF21934 (0.1–5 mg·kg−1) and Lu AF32615 (2–10 mg·kg−1) dose‐dependently inhibited hyperactivity induced by MK‐801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4−/−) mice, Lu AF21934 did not antagonize DOI‐induced head twitches. MK‐801‐induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg−1 and by Lu AF32615 at 10 mg·kg−1. In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg−1, while Lu AF32615 was active at 10 mg·kg−1. 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Experimental Approach Hyperactivity induced by MK‐801 or amphetamine and head twitches induced by 2,5‐dimethoxy‐4‐iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK‐801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively. Key Results Lu AF21934 (0.1–5 mg·kg−1) and Lu AF32615 (2–10 mg·kg−1) dose‐dependently inhibited hyperactivity induced by MK‐801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4−/−) mice, Lu AF21934 did not antagonize DOI‐induced head twitches. MK‐801‐induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg−1 and by Lu AF32615 at 10 mg·kg−1. In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg−1, while Lu AF32615 was active at 10 mg·kg−1. Conclusions and Implications We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>23714045</pmid><doi>10.1111/bph.12254</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content; Wiley Online Library All Journals; PubMed Central; Alma/SFX Local Collection
subjects Allosteric Regulation
Amphetamine
Anilides - pharmacology
Animals
Antipsychotic Agents - pharmacology
Cyclohexanecarboxylic Acids - pharmacology
Disease Models, Animal
Dizocilpine Maleate
Dose-Response Relationship, Drug
Excitatory Postsynaptic Potentials - drug effects
Hyperkinesis - drug therapy
Lu AF21934
Lu AF32615
Male
mGlu receptors
Mice
Motor Activity - drug effects
positive allosteric modulation
Rats
Receptors, Metabotropic Glutamate - drug effects
Research Papers
schizophrenia
Schizophrenia - chemically induced
Schizophrenia - drug therapy
title The antipsychotic‐like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents
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