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Nature Communications Aug 2023γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of...
γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.
Topics: Female; Humans; Neurosteroids; Pregnanolone; Receptors, GABA-A; Binding Sites; Sulfates; gamma-Aminobutyric Acid
PubMed: 37607940
DOI: 10.1038/s41467-023-40800-1 -
Psychopharmacology Dec 2023Reproductive experience (pregnancy and motherhood) leads to long-term changes in the neurobiological and hormonal features of anxiety in rats and humans. The aim of this...
OVERVIEW
Reproductive experience (pregnancy and motherhood) leads to long-term changes in the neurobiological and hormonal features of anxiety in rats and humans. The aim of this study was to examine whether reproductive experience alters the effects of two pharmacological treatments for anxiety, a benzodiazepine (diazepam) and a selective serotonin reuptake inhibitor (fluoxetine), on animal models of anxiety.
METHODS
In Experiment 1, virgin (n = 47) and age-matched mother (n = 50) rats at 1-month post-weaning were injected with diazepam (1.3 mg/kg or 1.7 mg/kg, i.p.) or vehicle, in the proestrus (high estradiol/progesterone/allopregnanolone) or metestrus (low estradiol/progesterone/allopregnanolone) phase of the estrous cycle 30 min prior to the elevated plus maze (EPM). In Experiment 2, virgin (n = 25) and mother rats (n = 20) were administered fluoxetine (10 mg/kg) or vehicle for 2 weeks prior to being tested on a Pavlovian fear conditioning and extinction protocol, and the EPM.
RESULTS
Replicating past research, in virgin rats, the low dose of diazepam produced anxiolytic-like effects in proestrus, but only the high dose was anxiolytic-like in metestrus. In contrast, in mother rats, both doses of diazepam were anxiolytic-like irrespective of estrous phase. Fluoxetine produced anxiogenic-like effects in virgin rats during fear extinction and the EPM, but had no behavioural effects in mothers. In contrast, fluoxetine increased plasma corticosterone levels measured 30-min post-EPM in mothers, but not virgin rats.
CONCLUSIONS
Reproductive experience alters the dose responsivity and efficacy of common anti-anxiety medications in female rats. These findings highlight the importance of considering reproductive status in studies on anxiety and its treatment.
Topics: Pregnancy; Humans; Rats; Female; Animals; Diazepam; Fluoxetine; Fear; Corticosterone; Anti-Anxiety Agents; Progesterone; Extinction, Psychological; Pregnanolone; Anxiety; Estradiol
PubMed: 37581635
DOI: 10.1007/s00213-023-06446-z -
Psychopharmacology Sep 2023This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines the landmark pharmacological journey of brexanolone as a... (Review)
Review
Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.
This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines the landmark pharmacological journey of brexanolone as a first-in-class neurosteroid antidepressant with significant advantages over traditional antidepressants. PPD is a neuroendocrine disorder that affects about 20% of mothers after childbirth and is characterized by symptoms including persistent sadness, fatigue, dysphoria, as well as disturbances in cognition, emotion, appetite, and sleep. The main pathology behind PPD is the postpartum reduction of neurosteroids, referred to as neurosteroid withdrawal, a concept pioneered by our preclinical studies. We developed neurosteroid replacement therapy (NRT) as a rational approach for treating PPD and other conditions related to neurosteroid deficiency, unveiling the power of neurosteroids as novel anxiolytic-antidepressants. The neurosteroid, brexanolone (BX), is a progesterone-derived allopregnanolone that rapidly relieves anxiety and mood deficits by activating GABA-A receptors, making it a transformational treatment for PPD. In 2019, the FDA approved BX, an intravenous formulation of allopregnanolone, as an NRT to treat PPD. In clinical studies, BX significantly improved PPD symptoms within hours of administration, with tolerable side effects including headache, dizziness, and somnolence. We identified the molecular mechanism of BX in a neuronal PPD-like milieu. The mechanism of BX involves activation of both synaptic and extrasynaptic GABA-A receptors, which promote tonic inhibition and serve as a key target for PPD and related conditions. Neurosteroids offer several advantages over traditional antidepressants, including rapid onset, unique mechanism, and lack of tolerance upon repeated use. Some limitations of BX therapy include lack of aqueous solubility, limited accessibility, hospitalization for treatment, lack of oral product, and serious adverse events at high doses. However, the unmet need for synthetic neurosteroids to address this critical condition supersedes these limitations. Recently, we developed novel hydrophilic neurosteroids with a superior profile and improved drug delivery. Overall, approval of BX is a major milestone in the field of neurotherapeutics, paving the way for the development of novel synthetic neurosteroids to treat depression, epilepsy, and status epilepticus.
Topics: Female; Humans; Neurosteroids; Depression, Postpartum; Pregnanolone; Receptors, GABA-A; Antidepressive Agents
PubMed: 37566239
DOI: 10.1007/s00213-023-06427-2 -
Acta Obstetricia Et Gynecologica... Oct 2023The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABA ) receptors...
INTRODUCTION
The mechanism underlying endometriosis-related pain remains poorly understood. Previous studies have indicated that γ-aminobutyric acid (GABA) type A (GABA ) receptors and GABAergic substances (eg endogenous neurosteroids) play important mechanistic roles in various pain conditions. Our primary objective was to compare GABA receptor function between women with endometriosis and healthy controls by performing a challenge test with diazepam, a GABA receptor agonist, using the saccadic eye velocity as the main outcome. The secondary objective was to investigate the relation between GABA receptor function and serum levels of allopregnanolone, an endogenous positive modulator of the GABA receptor, in the participating women.
MATERIAL AND METHODS
15 women with pelvic pain and laparoscopically confirmed endometriosis and 10 healthy, symptom-free, control women, aged 18-40 years, underwent the diazepam challenge test during the follicular phase of the menstrual cycle. Basal serum allopregnanolone levels were measured prior to diazepam injection.
RESULTS
Compared with healthy controls, women with pelvic pain and confirmed endometriosis had a significantly smaller change in saccadic eye velocity after GABA receptor stimulation with diazepam, indicating lower sensitivity to diazepam. The saccadic eye velocity response was not correlated with the serum allopregnanolone levels.
CONCLUSIONS
Women with painful endometriosis show altered GABA receptor function, depicted as a muted response to an exogenous GABA receptor agonist.
Topics: Female; Humans; Receptors, GABA-A; Pregnanolone; Endometriosis; gamma-Aminobutyric Acid; Diazepam; Gonadal Steroid Hormones; Pelvic Pain
PubMed: 36944570
DOI: 10.1111/aogs.14559 -
Biological Psychiatry Aug 2023Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders...
BACKGROUND
Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown.
METHODS
We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes.
RESULTS
The expression of δ subunit-containing GABA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS.
CONCLUSIONS
Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.
Topics: Mice; Animals; Pregnanolone; Receptors, GABA-A; Neurosteroids; Signal Transduction; gamma-Aminobutyric Acid
PubMed: 36736870
DOI: 10.1016/j.biopsych.2023.01.022