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TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia

GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2...

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Autores principales: Rajagopal, Lakshmi, Huang, Mei, Michael, Eric, Kwon, Sunoh, Meltzer, Herbert Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180114/
https://www.ncbi.nlm.nih.gov/pubmed/30093697
http://dx.doi.org/10.1038/s41386-018-0160-3
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author Rajagopal, Lakshmi
Huang, Mei
Michael, Eric
Kwon, Sunoh
Meltzer, Herbert Y.
author_facet Rajagopal, Lakshmi
Huang, Mei
Michael, Eric
Kwon, Sunoh
Meltzer, Herbert Y.
author_sort Rajagopal, Lakshmi
collection PubMed
description GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABA(A) α2,3 subtype-selective GABA(A) partial agonist and α(1/5) antagonist, and the neurosteroid, pregnenolone sulfate, a GABA(A) antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABA(A) agonists may be of benefit to treat CIAS.
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spelling pubmed-61801142019-04-12 TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia Rajagopal, Lakshmi Huang, Mei Michael, Eric Kwon, Sunoh Meltzer, Herbert Y. Neuropsychopharmacology Article GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABA(A) α2,3 subtype-selective GABA(A) partial agonist and α(1/5) antagonist, and the neurosteroid, pregnenolone sulfate, a GABA(A) antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABA(A) agonists may be of benefit to treat CIAS. Springer International Publishing 2018-07-23 2018-11 /pmc/articles/PMC6180114/ /pubmed/30093697 http://dx.doi.org/10.1038/s41386-018-0160-3 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Rajagopal, Lakshmi
Huang, Mei
Michael, Eric
Kwon, Sunoh
Meltzer, Herbert Y.
TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
title TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
title_full TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
title_fullStr TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
title_full_unstemmed TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
title_short TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABA(A) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
title_sort tpa-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via gaba(a) receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180114/
https://www.ncbi.nlm.nih.gov/pubmed/30093697
http://dx.doi.org/10.1038/s41386-018-0160-3
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