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

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Grotell , M , Abdurakhmanova , S , Elsilä , L V & Korpi , E R 2021 , ' Mice Lacking GABA(A) Receptor delta Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs ' , Frontiers in Pharmacology , vol. 12 , 706894 . https://doi.org/10.3389/fphar.2021.706894

Title: Mice Lacking GABA(A) Receptor delta Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
Author: Grotell, Milo; Abdurakhmanova, Shamsiiat; Elsilä, Lauri V.; Korpi, Esa R.
Contributor: University of Helsinki, Medicum
University of Helsinki, Department of Anatomy
University of Helsinki, Medicum
University of Helsinki, Esa Risto Korpi / Principal Investigator
Date: 2021-06-21
Language: eng
Number of pages: 12
Belongs to series: Frontiers in Pharmacology
ISSN: 1663-9812
URI: http://hdl.handle.net/10138/333885
Abstract: In the brain, extrasynaptically expressed ionotropic, delta subunit-containing gamma-aminobutyric acid A-type receptors (delta-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 delta-GABA(A)Rs (delta-KO) has been used to study the roles of delta-GABA(A)Rs in brain functions, because a specific antagonist of the delta-GABA(A)Rs is still lacking. We have previously observed with these delta-KO mice that activation of delta-GABA(A)Rs is needed for morphine-induced conditioning of place preference, and others have suggested that delta-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 delta-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 delta-GABA(A)Rs, was included as the positive control, and as expected, delta-KO mice produced a blunted pharmaco-EEG response to 6 mg/kg THIP. Pharmaco-EEGs showed notable differences between treatments but also differences between delta-KO mice and their wild-type littermates. Interestingly mephedrone (4-MMC, 5 mg/kg), an amphetamine-like stimulant, had reduced effects in the delta-KO mice. The responses to ethanol (1 g/kg), LSD (0.2 mg/kg), and morphine (20 mg/kg) were similar in delta-KO and wild-type mice. Since stimulants are not known to act on delta-GABA(A)Rs, our findings on pharmaco-EEG effects of 4-MMC suggest that delta-GABA(A)Rs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC.
Subject: pharmaco-EEG
extrasynaptic GABAA receptors
ethanol
opioids
stimulants
psychedelics
DEFICIENT MICE
OPIOID SYSTEM
A RECEPTORS
SUBTYPES
SENSITIVITY
GABOXADOL
MORPHINE
BEHAVIOR
SLEEP
RADIOELECTROENCEPHALOGRAPHY
3111 Biomedicine
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