Integrative insights into ε subunit-containing GABAA receptors: exploring non-canonical modulation by zolpidem

Zolpidem is a widely prescribed hypnotic agent that has been reported to produce paradoxical neurological effects in a subset of patients with conditions such as disorders of consciousness and other forms of neurological injury, including transient improvements in arousal and function. The mechanisms underlying these responses remain incompletely understood. This review critically synthesizes evidence supporting the hypothesis that non-canonical ε subunit-containing GABAA receptors, may contribute to these atypical effects of zolpidem. Evidence from heterologous expression systems indicates that incorporation of the ε subunit can alter GABAA receptor gating and reduce sensitivity to classical benzodiazepine-site ligands, with some studies reporting zolpidem-dependent modulation. However, these findings are derived primarily from recombinant systems and do not establish the existence, distribution, or functional significance of defined ε-containing receptor assemblies in native brain tissue. In vivo studies have reported altered ε subunit expression following neurological injury together with behavioural responses to zolpidem, although these associations remain correlative. Computational modelling and molecular docking studies further suggest the possibility of non-canonical ligand-receptor interactions, but these predictions have yet to be validated experimentally. Collectively, the available evidence identifies ε-containing GABAA receptors as a biologically plausible but unproven contributor to the paradoxical neurological effects of zolpidem. By integrating findings across molecular, experimental, and computational studies, this review highlights key limitations in the current evidence base and outlines priorities for future research aimed at determining whether ε-containing GABAA receptors play a causal role in zolpidem-induced neurological responses.