The immediate and maintained effects of neurosteroids on GABAA receptors

Belelli, Delia; Peters, John A.; Phillips, G.; Lambert, Jeremy J.

doi:10.1016/j.coemr.2022.100333

Cited by 4 publications

(2 citation statements)

References 54 publications

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“…Potentially complementing this effect, the steroid may increase the cell surface expression and/or enhance the spontaneous gating of the extrasynaptic α4β3δ GABA A Rs. Phosphorylation of the β3 subunit S408/409 residues plays a key role in both the facilitation of spontaneous gating and the increased cell surface receptor expression [35,[58][59][60][61]. Indeed, allopregnanolone had no effect on the tonic current of dentate granule cells obtained from a phosphorylation-resistant "knock-in" mouse expressing a β3 subunit 408/9 serine to alanine mutation [59].…”

Section: The Profile Of Neurosteroids and Synthetic Neuroactive Stero...mentioning

confidence: 99%

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

Mitchell,

Phillips,

Tench

et al. 2024

Biomolecules

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The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABAAR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABAARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABAARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed.

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Section: The Profile Of Neurosteroids and Synthetic Neuroactive Stero...mentioning

confidence: 99%

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

Mitchell,

Phillips,

Tench

et al. 2024

Biomolecules

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“…Neurosteroids are potent and effective neuromodulators synthesized from cholesterol in glial and neuronal cells of the central (CNS) and peripheral nervous systems (PNS). They act at extrasynaptic receptors, facilitating tonic inhibition (Chen et al, 2019;Belelli et al, 2022). With acute alcohol intake, the cerebral levels of allopregnanolone were found to be increased, whereas its levels were reduced during chronic alcohol consumption and withdrawal (Romeo et al, 1996).…”

Section: Gabaergic Interventions Inmentioning

confidence: 99%

GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential

Dharavath,

Pina-Leblanc,

Tang

et al. 2023

Front. Neural Circuits

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Alcohol is one of the most widely used substances. Alcohol use accounts for 5.1% of the global disease burden, contributes substantially to societal and economic costs, and leads to approximately 3 million global deaths yearly. Alcohol use disorder (AUD) includes various drinking behavior patterns that lead to short-term or long-lasting effects on health. Ethanol, the main psychoactive molecule acting in alcoholic beverages, directly impacts the GABAergic system, contributing to GABAergic dysregulations that vary depending on the intensity and duration of alcohol consumption. A small number of interventions have been developed that target the GABAergic system, but there are promising future therapeutic avenues to explore. This review provides an overview of the impact of alcohol on the GABAergic system, the current interventions available for AUD that target the GABAergic system, and the novel interventions being explored that in the future could be included among first-line therapies for the treatment of AUD.

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Modulation of sweet preference by neurosteroid-sensitive, δ-GABA_Areceptors in adult mouse gustatory insular cortex

Yevoo,

Fontanini,

Maffei

2024

Preprint

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Taste preference is a fundamental driver of feeding behavior influencing dietary choices and eating patterns. Extensive experimental evidence indicates that the gustatory cortex (GC) is engaged in taste perception, palatability and preference. However, our knowledge of the neural and neurochemical signals regulating taste preference is rather limited. Neuromodulators can affect preferences, though their effects on neural circuits for taste are incompletely understood. Neurosteroids are of particular interest in view of reports that systemic administration of the neurosteroid allopregnanolone, a potent modulator of tonic GABAergic inhibition, induces hyperphagia and increases intake of energy rich food in human and animal subjects. Tonic inhibition is a powerful modulator of circuit excitability and is primarily mediated by extrasynaptic GABAA receptors containing the delta subunit (δ-GABAARs). These receptors are widely distributed in the brain, but information regarding the expression of δ-GABAARs within gustatory circuits is lacking, and their role in taste preference has not been investigated. Here, we focused on GC to investigate whether activation of δ-GABAARs affects sweet taste preference in adult mice. Our data reveal that δ-GABAARs are expressed in multiple cell types within GC. These receptors mediate an allopregnanolone-sensitive tonic current and decrease sweet taste preference by altering the behavioral sensitivity to sucrose concentration in a cell type-specific manner. Our findings demonstrate that taste sensitivity and preference in the adult mammalian brain are modulated by tonic inhibition mediated by neurosteroid-activated δ-GABAARs in GC.

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The immediate and maintained effects of neurosteroids on GABAA receptors

Cited by 4 publications

References 54 publications

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential

Modulation of sweet preference by neurosteroid-sensitive, δ-GABA_Areceptors in adult mouse gustatory insular cortex

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The immediate and maintained effects of neurosteroids on GABAA receptors

Cited by 4 publications

References 54 publications

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

Neurosteroid Modulation of Synaptic and Extrasynaptic GABAA Receptors of the Mouse Nucleus Accumbens

GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential

Modulation of sweet preference by neurosteroid-sensitive, δ-GABAAreceptors in adult mouse gustatory insular cortex

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Modulation of sweet preference by neurosteroid-sensitive, δ-GABA_Areceptors in adult mouse gustatory insular cortex