Mice Lacking GABAA Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs

Abstract

In the brain, extrasynaptically expressed ionotropic, δ subunit-containing γ-aminobutyric acid A-type receptors (δ-GABAARs) 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-GABAARs (δ-KO) has been used to study the roles of δ-GABAARs in brain functions, because a specific antagonist of the δ-GABAARs is still lacking. We have previously observed with these δ-KO mice that activation of δ-GABAARs is needed for morphine-induced conditioning of place preference, and others have suggested that δ-GABAARs 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-GABAARs, 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-GABAARs, our findings on pharmaco-EEG effects of 4-MMC suggest that δ-GABAARs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC.

Comparative Assessment of TSPO Modulators on Electroencephalogram Activity and Exploratory Behavior

“…While the actions of TSPO ligands on EEG and behavior are distinct from benzodiazepines, they do share similarities with the actions of gaboxadol (THIP), a superagonist of GABA A receptors containing the δ-subunit ( Krogsgaard-Larsen et al, 2004 ; Meera et al, 2011 ). For example, gaboxadol induces immobility in the open field (7 mg/kg; ( Bowen et al, 2015 )), and enhances EEG δ frequency band power (6 mg/kg; ( van Lier et al, 2004 ; Winsky-Sommerer et al, 2007 ; Grotell et al, 2021 ). Intriguingly δ-subunit containing GABA A receptors are also sensitive to physiological levels of neurosteroids ( Stell et al, 2003 ; MacKenzie and Maguire, 2013 ).…”

High lactic acid levels in the brain contribute to the generation of focal slowing on the electroencephalogram

“…Synaptic GABAARs, including γ 2 subunits, are benzodiazepine-sensitive, whereas extrasynaptic GABAARs, including δ subunits, which are sensitive to gaboxadol. It is known from pharmaco-electroencephalography studies that the activation of GABAARs by benzodiazepines enhances EEG beta power, and using gaboxadol causes elevated delta power ( 33 ). In addition, H + from the extracellular space can activate a specific type of anion channel named PAC (proton-activated outwardly rectifying anion channel), which also mediates the influx of Cl − ( 34 ).…”

Neural effects of dopaminergic compounds revealed by multi-site electrophysiology and interpretable machine-learning

“…Whereas the effects of neuropsychopharmacological compounds are usually well understood at the molecular level, their impact on circuit mechanisms that mediate psychological functions remains largely elusive. Electroencephalography (EEG) or local field potential (LFP) recordings during compound administration—termed pharmaco-EEG (pEEG) or pharmaco-LFP (pLFP)—may reveal neurophysiological effects at the circuit level whose patterns are specific to a given compound or are specifically shared by a representative psychopharmacological class of compounds ( Itil, 1983 ; Dimpfel et al, 1986 ; Dimpfel et al, 1992 ; Dimpfel, 2009 ; Drinkenburg et al, 2016 ; Grotell et al, 2021 ). Despite their great contribution to describe certain patterns of neurophysiological effects of a large number of compounds in both humans and rodents, their translation into a mechanistic understanding regarding therapeutic action remains a challenge ( Gener et al, 2019 ; Delgado-Sallent et al, 2022 ).…”