The immediate and maintained effects of neurosteroids on GABA_A receptors

Allopregnanolone is an endogenous neurosteroid that acts in a rapid non-genomic manner to enhance the function of the GABA_A receptor (GABA_AR), the major inhibitory receptor in the mammalian central nervous system (CNS). Consequently, allopregnanolone elicits anxiolytic, antidepressant, anticonvulsant, analgesic and sedative effects. Endogenous allopregnanolone influences neural inhibition and behaviour, with perturbed neurosteroid levels implicated in depressive disorders. The approval of brexanolone (an allopregnanolone formulation) to treat postpartum depression (PPD) has encouraged optimism that they may provide a new approach to treat mood disorders. Elucidating how neurosteroids are distinguished from established GABA_AR-active drugs, e.g. benzodiazepines, may improve understanding of depressive disorders and aid drug development for psychiatric conditions. Here, we focus on research highlighting: (1) the acute interaction of neurosteroids with GABA_ARs incorporating the δ subunit (δ-GABA_AR) and (2) how neurosteroids may additionally act on a slower time scale to enhance expression of δ-GABA_ARs, thereby providing sustained therapeutic benefit.