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.
Highlights
Pharmaco-electroencephalography has been used as a method for distinguishing compounds between different drug classes in early drug development by observing changes in neural oscillations (Dimpfel et al, 1986; Dimpfel, 2003; Drinkenburg et al, 2015)
Male mice were used to reduce the possibility of producing confounding factors, as the ovarian cycle in female mice regulates the endogenous levels of neurosteroids and the expression of δ-GABAARs (Bäckström et al, 2003; Maguire et al, 2005)
These results indicate that the mouse model that we used responded to the δ-GABAAR superagonist THIP as predicted
Summary
Pharmaco-electroencephalography (pharmaco-EEG) has been used as a method for distinguishing compounds between different drug classes in early drug development by observing changes in neural oscillations (Dimpfel et al, 1986; Dimpfel, 2003; Drinkenburg et al, 2015). Drug-Induced Alterations in Pharmaco-EEG activation (Dimpfel et al, 1989; Ferger and Kuschinsky, 1995). This effect might be produced by disinhibitory mechanism, as opioids are known to presynaptically inhibit the release of the main inhibitory transmitter γ-aminobutyric acid (GABA). Synaptic GABAARs often contain a γ2-subunit and are sensitive to benzodiazepines, while those located extrasynaptically often include a δ-subunit and are benzodiazepine-insensitive (Brickley and Mody, 2012). Both of those receptor types are abundant, e.g., in the cortex and thalamus (Wisden et al, 1992).
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