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Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex

The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors). The orexin system projects widely through the brain and functions as an interface between m...

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Autores principales: Aluisio, Leah, Fraser, Ian, Berdyyeva, Tamara, Tryputsen, Volha, Shireman, Brock T., Shoblock, James, Lovenberg, Timothy, Dugovic, Christine, Bonaventure, Pascal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033200/
https://www.ncbi.nlm.nih.gov/pubmed/24904253
http://dx.doi.org/10.3389/fnins.2014.00107
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author Aluisio, Leah
Fraser, Ian
Berdyyeva, Tamara
Tryputsen, Volha
Shireman, Brock T.
Shoblock, James
Lovenberg, Timothy
Dugovic, Christine
Bonaventure, Pascal
author_facet Aluisio, Leah
Fraser, Ian
Berdyyeva, Tamara
Tryputsen, Volha
Shireman, Brock T.
Shoblock, James
Lovenberg, Timothy
Dugovic, Christine
Bonaventure, Pascal
author_sort Aluisio, Leah
collection PubMed
description The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors). The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward, and emotion. Recent studies have demonstrated that orexins and glutamate interact at the synaptic level and that orexins facilitate glutamate actions. We tested the hypothesis that orexins modulate glutamate signaling via OX1 receptors by monitoring levels of glutamate in frontal cortex of freely moving mice using enzyme coated biosensors under inhibited OX1 receptor conditions. MK-801, an NMDA receptor antagonist, was administered subcutaneously (0.178 mg/kg) to indirectly disinhibit pyramidal neurons and therefore increase cortical glutamate release. In wild-type mice, pretreatment with the OX1 receptor antagonist GSK-1059865 (10 mg/kg S.C.) which had no effect by itself, significantly attenuated the cortical glutamate release elicited by MK-801. OX1 receptor knockout mice had a blunted glutamate release response to MK-801 and exhibited about half of the glutamate release observed in wild-type mice in agreement with the data obtained with transient blockade of OX1 receptors. These results indicate that pharmacological (transient) or genetic (permanent) inhibition of the OX1 receptor similarly interfere with glutamatergic function in the cortex. Selectively targeting the OX1 receptor with an antagonist may normalize hyperglutamatergic states and thus may represent a novel therapeutic strategy for the treatment of various psychiatric disorders associated with hyperactive states.
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spelling pubmed-40332002014-06-05 Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex Aluisio, Leah Fraser, Ian Berdyyeva, Tamara Tryputsen, Volha Shireman, Brock T. Shoblock, James Lovenberg, Timothy Dugovic, Christine Bonaventure, Pascal Front Neurosci Pharmacology The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors). The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward, and emotion. Recent studies have demonstrated that orexins and glutamate interact at the synaptic level and that orexins facilitate glutamate actions. We tested the hypothesis that orexins modulate glutamate signaling via OX1 receptors by monitoring levels of glutamate in frontal cortex of freely moving mice using enzyme coated biosensors under inhibited OX1 receptor conditions. MK-801, an NMDA receptor antagonist, was administered subcutaneously (0.178 mg/kg) to indirectly disinhibit pyramidal neurons and therefore increase cortical glutamate release. In wild-type mice, pretreatment with the OX1 receptor antagonist GSK-1059865 (10 mg/kg S.C.) which had no effect by itself, significantly attenuated the cortical glutamate release elicited by MK-801. OX1 receptor knockout mice had a blunted glutamate release response to MK-801 and exhibited about half of the glutamate release observed in wild-type mice in agreement with the data obtained with transient blockade of OX1 receptors. These results indicate that pharmacological (transient) or genetic (permanent) inhibition of the OX1 receptor similarly interfere with glutamatergic function in the cortex. Selectively targeting the OX1 receptor with an antagonist may normalize hyperglutamatergic states and thus may represent a novel therapeutic strategy for the treatment of various psychiatric disorders associated with hyperactive states. Frontiers Media S.A. 2014-05-20 /pmc/articles/PMC4033200/ /pubmed/24904253 http://dx.doi.org/10.3389/fnins.2014.00107 Text en Copyright © 2014 Aluisio, Fraser, Berdyyeva, Tryputsen, Shireman, Shoblock, Lovenberg, Dugovic and Bonaventure. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Aluisio, Leah
Fraser, Ian
Berdyyeva, Tamara
Tryputsen, Volha
Shireman, Brock T.
Shoblock, James
Lovenberg, Timothy
Dugovic, Christine
Bonaventure, Pascal
Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex
title Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex
title_full Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex
title_fullStr Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex
title_full_unstemmed Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex
title_short Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex
title_sort pharmacological or genetic orexin1 receptor inhibition attenuates mk-801 induced glutamate release in mouse cortex
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033200/
https://www.ncbi.nlm.nih.gov/pubmed/24904253
http://dx.doi.org/10.3389/fnins.2014.00107
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