Does oxytocin interact with GABAA receptors?

Abstract

Ethanol at low millimolar levels enhances the engagement of gamma-aminobutyric acid type A receptors incorporating the δ subunit (δ-GABAAR). In the present study, utilizing [3H]muscimol and [3H]EBOB binding assays, we examined the impact of oxytocin on GABA agonist binding to cerebellar and forebrain membranes from male and female rats, as well as recombinant GABAA α6β3γ2 and α6β3δ receptors. In cerebellar membranes, oxytocin exhibited no significant alteration in [3H]muscimol binding, indicating an absence of influence on GABA agonist binding to cerebellar tissues in rats of both genders. Conversely, in forebrain membranes, oxytocin displayed a slight contrasting effects on basal [3H]EBOB binding in male and female rats. In the male forebrain, oxytocin enhances [3H]EBOB binding, suggesting counteracting effect against GABA. In contrast, in the female forebrain, oxytocin reduces [3H]EBOB binding, implying a potentiating effect on GABA activity on GABA-induced [3H]EBOB displacement. Furthermore, utilizing recombinant α6β3γ2 and α6β3δ receptors, oxytocin demonstrated differential effects on [3H]EBOB binding. An increased binding percentage to α6β3γ2 receptors oxytocin did not influence the binding activity of [3H]EBOB binding in that receptor compared to control, while decreasing [3H]EBOB binding to α6β3δ receptors, suggesting increased inhibitory activity. Additionally, molecular docking was employed to explore potential binding interactions between oxytocin and the GABAA α6β3δ receptor, focusing on the subunit interfaces involving the δ subunit. Conventional docking to a rigid receptor model resulted in less optimal binding interactions than induced fit docking (IFD) that allows for flexible protein side chains during the docking process. The findings underscore the importance of polar interactions and optimal hydrophobic residue placement for oxytocin’s binding affinity.