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Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs

In the brain, extrasynaptically expressed ionotropic, δ subunit-containing γ-aminobutyric acid A-type receptors (δ-GABA(A)Rs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused via drug-induced modulation of receptor ionophores af...

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Autores principales: Grotell, Milo, Abdurakhmanova, Shamsiiat, Elsilä, Lauri V., Korpi, Esa R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255781/
https://www.ncbi.nlm.nih.gov/pubmed/34234684
http://dx.doi.org/10.3389/fphar.2021.706894
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author Grotell, Milo
Abdurakhmanova, Shamsiiat
Elsilä, Lauri V.
Korpi, Esa R.
author_facet Grotell, Milo
Abdurakhmanova, Shamsiiat
Elsilä, Lauri V.
Korpi, Esa R.
author_sort Grotell, Milo
collection PubMed
description In the brain, extrasynaptically expressed ionotropic, δ subunit-containing γ-aminobutyric acid A-type receptors (δ-GABA(A)Rs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused via drug-induced modulation of receptor ionophores affecting chloride ion-mediated inhibitory tonic currents. Often, a transgenic mouse model genetically lacking the δ-GABA(A)Rs (δ-KO) has been used to study the roles of δ-GABA(A)Rs in brain functions, because a specific antagonist of the δ-GABA(A)Rs is still lacking. We have previously observed with these δ-KO mice that activation of δ-GABA(A)Rs is needed for morphine-induced conditioning of place preference, and others have suggested that δ-GABA(A)Rs act as targets selectively for low doses of ethanol. Furthermore, activation of these receptors via drug-mediated agonism induces a robust increase in the slow-wave frequency bands of electroencephalography (EEG). Here, we tested δ-KO mice (compared to littermate wild-type controls) for the pharmaco-EEG responses of a broad spectrum of pharmacologically different drug classes, including alcohol, opioids, stimulants, and psychedelics. Gaboxadol (THIP), a known superagonist of δ-GABA(A)Rs, was included as the positive control, and as expected, δ-KO mice produced a blunted pharmaco-EEG response to 6 mg/kg THIP. Pharmaco-EEGs showed notable differences between treatments but also differences between δ-KO mice and their wild-type littermates. Interestingly mephedrone (4-MMC, 5 mg/kg), an amphetamine-like stimulant, had reduced effects in the δ-KO mice. The responses to ethanol (1 g/kg), LSD (0.2 mg/kg), and morphine (20 mg/kg) were similar in δ-KO and wild-type mice. Since stimulants are not known to act on δ-GABA(A)Rs, our findings on pharmaco-EEG effects of 4-MMC suggest that δ-GABA(A)Rs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC.
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spelling pubmed-82557812021-07-06 Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs Grotell, Milo Abdurakhmanova, Shamsiiat Elsilä, Lauri V. Korpi, Esa R. Front Pharmacol Pharmacology In the brain, extrasynaptically expressed ionotropic, δ subunit-containing γ-aminobutyric acid A-type receptors (δ-GABA(A)Rs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused via drug-induced modulation of receptor ionophores affecting chloride ion-mediated inhibitory tonic currents. Often, a transgenic mouse model genetically lacking the δ-GABA(A)Rs (δ-KO) has been used to study the roles of δ-GABA(A)Rs in brain functions, because a specific antagonist of the δ-GABA(A)Rs is still lacking. We have previously observed with these δ-KO mice that activation of δ-GABA(A)Rs is needed for morphine-induced conditioning of place preference, and others have suggested that δ-GABA(A)Rs act as targets selectively for low doses of ethanol. Furthermore, activation of these receptors via drug-mediated agonism induces a robust increase in the slow-wave frequency bands of electroencephalography (EEG). Here, we tested δ-KO mice (compared to littermate wild-type controls) for the pharmaco-EEG responses of a broad spectrum of pharmacologically different drug classes, including alcohol, opioids, stimulants, and psychedelics. Gaboxadol (THIP), a known superagonist of δ-GABA(A)Rs, was included as the positive control, and as expected, δ-KO mice produced a blunted pharmaco-EEG response to 6 mg/kg THIP. Pharmaco-EEGs showed notable differences between treatments but also differences between δ-KO mice and their wild-type littermates. Interestingly mephedrone (4-MMC, 5 mg/kg), an amphetamine-like stimulant, had reduced effects in the δ-KO mice. The responses to ethanol (1 g/kg), LSD (0.2 mg/kg), and morphine (20 mg/kg) were similar in δ-KO and wild-type mice. Since stimulants are not known to act on δ-GABA(A)Rs, our findings on pharmaco-EEG effects of 4-MMC suggest that δ-GABA(A)Rs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC. Frontiers Media S.A. 2021-06-21 /pmc/articles/PMC8255781/ /pubmed/34234684 http://dx.doi.org/10.3389/fphar.2021.706894 Text en Copyright © 2021 Grotell, Abdurakhmanova, Elsilä and Korpi. https://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
Grotell, Milo
Abdurakhmanova, Shamsiiat
Elsilä, Lauri V.
Korpi, Esa R.
Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
title Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
title_full Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
title_fullStr Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
title_full_unstemmed Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
title_short Mice Lacking GABA(A) Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
title_sort mice lacking gaba(a) receptor δ subunit have altered pharmaco-eeg responses to multiple drugs
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255781/
https://www.ncbi.nlm.nih.gov/pubmed/34234684
http://dx.doi.org/10.3389/fphar.2021.706894
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