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Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice
Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGl...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600181/ https://www.ncbi.nlm.nih.gov/pubmed/31174329 http://dx.doi.org/10.3390/ijms20112781 |
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author | Cieślik, Paulina Radulska, Adrianna Pelikant-Małecka, Iwona Płoska, Agata Kalinowski, Leszek Wierońska, Joanna M |
author_facet | Cieślik, Paulina Radulska, Adrianna Pelikant-Małecka, Iwona Płoska, Agata Kalinowski, Leszek Wierońska, Joanna M |
author_sort | Cieślik, Paulina |
collection | PubMed |
description | Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu(2) and M(4) subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu(2) and M(4) receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu(2) receptor, and VU152100 (0.25−0.5 mg/kg), a positive allosteric modulator of the M(4) receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug–drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M(4) and mGlu(2) receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia. |
format | Online Article Text |
id | pubmed-6600181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66001812019-07-16 Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice Cieślik, Paulina Radulska, Adrianna Pelikant-Małecka, Iwona Płoska, Agata Kalinowski, Leszek Wierońska, Joanna M Int J Mol Sci Article Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu(2) and M(4) subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu(2) and M(4) receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu(2) receptor, and VU152100 (0.25−0.5 mg/kg), a positive allosteric modulator of the M(4) receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug–drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M(4) and mGlu(2) receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia. MDPI 2019-06-06 /pmc/articles/PMC6600181/ /pubmed/31174329 http://dx.doi.org/10.3390/ijms20112781 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cieślik, Paulina Radulska, Adrianna Pelikant-Małecka, Iwona Płoska, Agata Kalinowski, Leszek Wierońska, Joanna M Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice |
title | Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice |
title_full | Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice |
title_fullStr | Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice |
title_full_unstemmed | Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice |
title_short | Reversal of MK-801-Induced Disruptions in Social Interactions and Working Memory with Simultaneous Administration of LY487379 and VU152100 in Mice |
title_sort | reversal of mk-801-induced disruptions in social interactions and working memory with simultaneous administration of ly487379 and vu152100 in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600181/ https://www.ncbi.nlm.nih.gov/pubmed/31174329 http://dx.doi.org/10.3390/ijms20112781 |
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