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 |
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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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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.</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.
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><subject>Allosteric Regulation</subject><subject>Amphetamine</subject><subject>Anilides - pharmacology</subject><subject>Animals</subject><subject>Antipsychotic Agents - pharmacology</subject><subject>Cyclohexanecarboxylic Acids - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Dizocilpine Maleate</subject><subject>Dose-Response Relationship, Drug</subject><subject>Excitatory Postsynaptic Potentials - drug effects</subject><subject>Hyperkinesis - drug therapy</subject><subject>Lu AF21934</subject><subject>Lu AF32615</subject><subject>Male</subject><subject>mGlu receptors</subject><subject>Mice</subject><subject>Motor Activity - drug effects</subject><subject>positive allosteric modulation</subject><subject>Rats</subject><subject>Receptors, Metabotropic Glutamate - drug effects</subject><subject>Research Papers</subject><subject>schizophrenia</subject><subject>Schizophrenia - chemically induced</subject><subject>Schizophrenia - drug therapy</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1OxCAUhYnR6Di68AVME9dVoDClGxM1_iUmutA1ofTWQWmpQDWz8xF8Rp9EHH-i3AUk58u53HsQ2iF4n6RzUA_zfUIpZytoQlg5y3khyCqaYIzLnBAhNtBmCA8YJ7Hk62iDFiVhmPEJermdQ6b6aIaw0HMXjX5_fbPmETJoW9AxZK7NBhdMNM8JtNaFCN7orHPNaFV0fkl0EFXtondDku7tGFWnImTduR1Z5kHDsCRNn3nXQB_DFlprlQ2w_X1P0d3Z6e3JRX51fX55cnSVD1QwlvOmqlUrZoqCUAIr2vAGcKsqhUWaHGMNHCirao3rdibahFRFEjQVmnNFiyk6_PIdxrqDRqfeXlk5eNMpv5BOGflf6c1c3rtnWZRpiammaO_bwLunEUKUD270ffqzJJyKGcMVrRK1-7fNr__PohNw8AW8GAuLX51g-ZmgTAnKZYLy-OZi-Sg-AF1nkm0</recordid><startdate>201308</startdate><enddate>201308</enddate><creator>Sławińska, Anna</creator><creator>Wierońska, Joanna M</creator><creator>Stachowicz, Katarzyna</creator><creator>Marciniak, Marcin</creator><creator>Łasoń‐Tyburkiewicz, Magdalena</creator><creator>Gruca, Piotr</creator><creator>Papp, Mariusz</creator><creator>Kusek, Magdalena</creator><creator>Tokarski, Krzysztof</creator><creator>Doller, Darío</creator><creator>Pilc, Andrzej</creator><general>Blackwell Publishing Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope></search><sort><creationdate>201308</creationdate><title>The antipsychotic‐like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents</title><author>Sławińska, Anna ; Wierońska, Joanna M ; Stachowicz, Katarzyna ; Marciniak, Marcin ; Łasoń‐Tyburkiewicz, Magdalena ; Gruca, Piotr ; Papp, Mariusz ; Kusek, Magdalena ; Tokarski, Krzysztof ; Doller, Darío ; Pilc, Andrzej</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2844-5d9baf86a2e8a80a2d5de0fa9a0811100ce5e249bc0bf68f80a93111c28c55a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Allosteric Regulation</topic><topic>Amphetamine</topic><topic>Anilides - pharmacology</topic><topic>Animals</topic><topic>Antipsychotic Agents - pharmacology</topic><topic>Cyclohexanecarboxylic Acids - pharmacology</topic><topic>Disease Models, Animal</topic><topic>Dizocilpine Maleate</topic><topic>Dose-Response Relationship, Drug</topic><topic>Excitatory Postsynaptic Potentials - drug effects</topic><topic>Hyperkinesis - drug therapy</topic><topic>Lu AF21934</topic><topic>Lu AF32615</topic><topic>Male</topic><topic>mGlu receptors</topic><topic>Mice</topic><topic>Motor Activity - drug effects</topic><topic>positive allosteric modulation</topic><topic>Rats</topic><topic>Receptors, Metabotropic Glutamate - drug effects</topic><topic>Research Papers</topic><topic>schizophrenia</topic><topic>Schizophrenia - chemically induced</topic><topic>Schizophrenia - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><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><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sławińska, Anna</au><au>Wierońska, Joanna M</au><au>Stachowicz, Katarzyna</au><au>Marciniak, Marcin</au><au>Łasoń‐Tyburkiewicz, Magdalena</au><au>Gruca, Piotr</au><au>Papp, Mariusz</au><au>Kusek, Magdalena</au><au>Tokarski, Krzysztof</au><au>Doller, Darío</au><au>Pilc, Andrzej</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The antipsychotic‐like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2013-08</date><risdate>2013</risdate><volume>169</volume><issue>8</issue><spage>1824</spage><epage>1839</epage><pages>1824-1839</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>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.</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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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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