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Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists
Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA(A) receptors and balances th...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218123/ https://www.ncbi.nlm.nih.gov/pubmed/32435195 http://dx.doi.org/10.3389/fphar.2020.00594 |
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author | Abdurakhmanova, Shamsiiat Grotell, Milo Kauhanen, Jenna Linden, Anni-Maija Korpi, Esa R. Panula, Pertti |
author_facet | Abdurakhmanova, Shamsiiat Grotell, Milo Kauhanen, Jenna Linden, Anni-Maija Korpi, Esa R. Panula, Pertti |
author_sort | Abdurakhmanova, Shamsiiat |
collection | PubMed |
description | Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA(A) receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABA(A) receptor δ subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor α-fluoromethylhistidine (αFMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and δ-containing subunit GABA(A) receptors are involved in mediating GABA response. |
format | Online Article Text |
id | pubmed-7218123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-72181232020-05-20 Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists Abdurakhmanova, Shamsiiat Grotell, Milo Kauhanen, Jenna Linden, Anni-Maija Korpi, Esa R. Panula, Pertti Front Pharmacol Pharmacology Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA(A) receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABA(A) receptor δ subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor α-fluoromethylhistidine (αFMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and δ-containing subunit GABA(A) receptors are involved in mediating GABA response. Frontiers Media S.A. 2020-05-06 /pmc/articles/PMC7218123/ /pubmed/32435195 http://dx.doi.org/10.3389/fphar.2020.00594 Text en Copyright © 2020 Abdurakhmanova, Grotell, Kauhanen, Linden, Korpi and Panula http://creativecommons.org/licenses/by/4.0/ 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) and the copyright owner(s) 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 Abdurakhmanova, Shamsiiat Grotell, Milo Kauhanen, Jenna Linden, Anni-Maija Korpi, Esa R. Panula, Pertti Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists |
title | Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists |
title_full | Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists |
title_fullStr | Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists |
title_full_unstemmed | Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists |
title_short | Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA(A) Receptors to Histamine Receptor 3 Antagonists |
title_sort | increased sensitivity of mice lacking extrasynaptic δ-containing gaba(a) receptors to histamine receptor 3 antagonists |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218123/ https://www.ncbi.nlm.nih.gov/pubmed/32435195 http://dx.doi.org/10.3389/fphar.2020.00594 |
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