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

Milo Grotell; Shamsiiat Abdurakhmanova; Lauri V Elsilä; Esa R Korpi

doi:10.3389/fphar.2021.706894

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

Front Pharmacol. 2021 Jun 21:12:706894. doi: 10.3389/fphar.2021.706894. eCollection 2021.

Authors

Milo Grotell¹, Shamsiiat Abdurakhmanova², Lauri V Elsilä¹, Esa R Korpi¹

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
² Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Abstract

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

Keywords: ethanol; extrasynaptic GABAA receptors; opioids; pharmaco-EEG; psychedelics; stimulants.