Neurosteroids: endogenous regulators of the GABAA receptor

Belelli, Delia; Lambert, Jeremy J.

doi:10.1038/nrn1703

Cited by 1,026 publications

(946 citation statements)

References 108 publications

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“…Specifically, results from recombinant GABA A receptors demonstrate that α subunit composition has a modest, albeit significant, effect on potency and no effect on efficacy for the positive A-ring reduced derivatives at recombinant α x β 1 γ 2L receptors. Substitution of different β subunit isoforms is without effect (for review, Belelli and Lambert, 2005;Belelli et al, 2006). With respect to α subunit composition, α 6 -containing recombinant receptors show the greatest sensitivity to modulation by positive neurosteroids, and those containing α 1 or α 3 subunits are slightly more sensitive than those containing α 2 or α 4 (for review Belelli et al, 2002).…”

Section: Neurosteroidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Naturally occurring neurosteroids are synthesized from cholesterol in both peripheral organs and in the central nervous system (CNS), primarily by glial cells, and can be classified as positive (enhancing) or negative (blocking) allosteric modulators of the GABA A receptor (for review, Baulieu, 1998;Compagnone and Mellon, 2000;Belelli and Lambert, 2005). Synthetic steroids, including anesthetics such as alphaxalone and ganaxolone (for review, Belelli and Lambert, 2005) and the anabolic androgenic steroids (AAS) (for review, Clark et al, 2004;2006) also act as allosteric modulators of the GABA A receptor. Reproductive biologists have demonstrated an indisputable role for nuclear hormone receptor-mediated steroid signaling in governing reproductive processes (for review, Course and Korach, 1998) and neuroendocrinologists have firmly established that allosteric modulation γ-aminobutyric acid type A (GABA A ) receptors has a critical role in mediating aggression, stress and anxiety; behaviors that are known to vary with hormonal state (for review, Finn et al, 2004;Henderson and Jorge, 2004;Smith, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson

2007

Neuropharmacology

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The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through nongenomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of γ-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

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Section: Neurosteroidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson

2007

Neuropharmacology

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“…Allopregnanolone (ALLO; 3α-hydroxy-5α-pregnan-20-one) is a potent positive modulator of GABA A receptors, and its allosteric activity at GABA A receptors is thought to underlie ALLO's profile as an anticonvulsant, anxiolytic, locomotor stimulant, and hypnotic [2]. These behavioral effects of ALLO are similar to those exhibited by ethanol, which exerts some of its effects through an interaction with GABA A receptors (for review, see [18]).…”

Section: Introductionmentioning

confidence: 99%

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

Ford

Mark

Nickel

et al. 2007

Behavioural Brain Research

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Although systemic allopregnanolone (ALLO; a positive modulator of GABA A receptors) has been shown to enhance ethanol-reinforced responding and to modulate drinking patterns in rodents, the effects of centrally administered ALLO on ethanol intake are not known. The current work examined the effects of intracranial ALLO on operant ethanol self-administration in food-and water-satiated mice, with a procedure designed to estimate ALLO's influence on appetitive versus consummatory processes. Male C57BL/6J (B6) mice were trained to press an ethanol-appropriate lever by being reinforced with 30-min of continuous access to a 10% ethanol solution. Following surgical implantation of a guide cannula aimed at the lateral ventricle and subsequent habituation to vehicle infusions, ALLO (50-400 ng; ICV) was delivered immediately prior to session start. ALLO doses of 100 and 400 ng were further evaluated for their effects on locomotor behavior within activity chambers. ALLO selectively modulated ethanol intake patterns associated with the onset and maintenance of self-administration, while leaving appetitive (i.e., ethanol seeking) measures unaltered. The effects of ALLO on drinking patterns were dissociable from changes in locomotor behavior, as evidenced by the absence of ALLO's influence on response frequency and horizontal distance traveled. These findings support the premise that manipulations in brain ALLO levels may influence the regulatory processes governing ethanol consumption.

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“…Allopregnanolone is a potent, endogenously produced neuroactive steroid that acts as a positive allosteric modulator (PAM) on a broad range of γ‐aminobutyric acid type A receptor (GABA A R) isoforms12, 13, 14, 15, 16 expressed throughout the brain, including those that mediate either phasic or tonic inhibition 17, 18, 19. Extrasynaptic receptors containing the δ‐subunit that mediate tonic inhibition are particularly sensitive to modulation by neurosteroids 18.…”

mentioning

confidence: 99%

Brexanolone as adjunctive therapy in super‐refractory status epilepticus

Rosenthal

Claassen

Wainwright

et al. 2017

Annals of Neurology

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ObjectiveSuper‐refractory status epilepticus (SRSE) is a life‐threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of brexanolone (USAN; formerly SAGE‐547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open‐label evaluation of brexanolone response during and after anesthetic third‐line agent (TLA) weaning.MethodsPatients receiving TLAs for SRSE control were eligible for open‐label, 1‐hour brexanolone loading infusions, followed by maintenance infusion. After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance. After 4 days, the brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow‐up.ResultsTwenty‐five patients received open‐label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty‐two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24 hours.InterpretationIn an open‐label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342–352

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Neurosteroids: endogenous regulators of the GABAA receptor

Cited by 1,026 publications

References 108 publications

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

Brexanolone as adjunctive therapy in super‐refractory status epilepticus

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