The role of allopregnanolone in depressive-like behaviors: Focus on neurotrophic proteins

Abstract

Allopregnanolone (3α,5α-tetrahydroprogesterone; pharmaceutical formulation: brexanolone) is a neurosteroid that has recently been approved for the treatment of postpartum depression, promising to fill part of a long-lasting gap in the effectiveness of pharmacotherapies for depressive disorders. In this review, we explore the experimental research that characterized the antidepressant-like effects of allopregnanolone, with a particular focus on the neurotrophic adaptations induced by this neurosteroid in preclinical studies. We demonstrate that there is a consistent decrease in allopregnanolone levels in limbic brain areas in rodents submitted to stress-induced models of depression, such as social isolation and chronic unpredictable stress. Further, both the drug-induced upregulation of allopregnanolone or its direct administration reduce depressive-like behaviors in models such as the forced swim test. The main drugs of interest that upregulate allopregnanolone levels are selective serotonin reuptake inhibitors (SSRIs), which present the neurosteroidogenic property even in lower, non-SSRI doses. Finally, we explore how these antidepressant-like behaviors are related to neurogenesis, particularly in the hippocampus. The protagonist in this mechanism is likely the brain-derived neurotrophic factor (BFNF), which is decreased in animal models of depression and may be restored by the normalization of allopregnanolone levels. The role of an interaction between GABA and the neurotrophic mechanisms needs to be further investigated.

Keywords: 3α,5α-tetrahydroprogesterone; BDNF; BDNF, brain-derived neurotrophic factor; Brexanolone; CSF, cerebrospinal fluid; CUS, chronic unpredictable stress; Depression; EKR, extracellular signal-regulated kinase; FST, forced swim test; GABA, γ-aminobutyric acid; GABAAR, GABA type A receptor; HSD, hydroxysteroid dehydrogenase; NGF, nerve growth factor; Neurosteroid; PTSD, post-traumatic stress disorder; PXR, pregnane xenobiotic receptor; SBSS, selective brain steroidogenic stimulant; SSRI, selective serotonin reuptake inhibitor; Selective brain steroidogenic stimulant; THP, tetrahydroprogesterone; TSPO, 18 kDa translocator protein; TrkB, tropomyosin receptor kinase B; USV, ultrasonic vocalization.