Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience

Abstract

The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABAA receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…The neurosteroid brexanolone allosterically enhances GABAA receptor function and has antidepressant and anxiolytic effects (Lüscher and Möhler, 2019). However, there is also recent evidence to suggest that GABA antagonism can be therapeutic for emotional disorders, in support of the hypothesis presented here that these disorders involve overinhibition in the PFC.…”

“…Most studies support the conclusion that glutamatergic activity in the PFC is reduced by chronic stress (Popoli et al, 2011;Musazzi et al, 2015). On the inhibitory side, the GABAergic deficit hypothesis (Lüscher et al, 2011;Lüscher and Möhler, 2019) is prevalent but has been challenged by others suggesting increased inhibitory neurotransmission in the PFC following chronic stress (McKlveen et al, 2016). Our work also challenged the GABAergic deficit hypothesis of stress and emotional dysfunction when we discovered that chronic stress increased the number of parvalbumin (PV) interneurons in the PFC, suggesting increased activity of this inhibitory cell population (Shepard et al, 2016;Shepard and Coutellier, 2018).…”

Antidepressant mechanism of classical herbal formula lily bulb and Rehmannia decoction: insights from gene expression profile of medial prefrontal cortex of mice with stress‐induced depression‐like behavior

“…Our data showed that these DEGs were mainly enriched in the neurotrophin signaling pathway, insulin signaling pathway, alcoholism, GABAergic synapse, glutamatergic synapse, amphetamine addiction, MAPK signaling pathway, PI3K‐Akt signaling pathway and circadian rhythm (Table ). Interestingly, these signaling pathways are involved in the pathophysiology and treatment of depression . For example, GABA and glutamate neurotransmitter deficits are used to explain the neurobiological abnormalities associated with MDD, which has been well‐accepted .…”

Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments

“…Mice in which the production of specific subunits of the GABA receptors was blocked or reduced through genetic manipulation have been observed to exhibit depression-like behaviours, as well as physiopathological features which are typical of animal models of MDD. Overall, these findings indicate that alterations in GABA neurotransmission could play a role in the development of MDD by inducing a disruption of the stress response system [52,53].…”

“…This association makes mGlu5 receptors an attractive target for indirectly modulating NMDA receptor function, and different compounds acting as negative modulators of mGlu5 receptors demonstrated an antidepressant-like activity in animal models [144]. Concerning the GABAergic system, emerging evidence indicates that drugs enhancing the function of specific GABA receptors exert an antidepressant action, thereby supporting the GABAergic deficit hypothesis of depression [52].…”