Neurosteroid Modulation of Synaptic and Extrasynaptic GABA A Receptors of the Mouse Nucleus Accumbens.

Autor: Mitchell SJ; Division of Cellular & Systems Medicine, School of Medicine, Medical Sciences Institute, Dundee University, Dow Street, Dundee DD1 5HL, UK., Phillips GD; Division of Cellular & Systems Medicine, School of Medicine, Medical Sciences Institute, Dundee University, Dow Street, Dundee DD1 5HL, UK., Tench B; Division of Cellular & Systems Medicine, School of Medicine, Medical Sciences Institute, Dundee University, Dow Street, Dundee DD1 5HL, UK., Li Y; Division of Cellular & Systems Medicine, School of Medicine, Medical Sciences Institute, Dundee University, Dow Street, Dundee DD1 5HL, UK., Belelli D; Division of Cellular & Systems Medicine, School of Medicine, Medical Sciences Institute, Dundee University, Dow Street, Dundee DD1 5HL, UK., Martin SJ; Division of Cellular & Systems Medicine, School of Medicine, Medical Sciences Institute, Dundee University, Dow Street, Dundee DD1 5HL, UK., Swinny JD; School of Pharmacy & Biomedical Sciences, St. Michael's Building, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, UK., Kelly L; School of Pharmacy & Biomedical Sciences, St. Michael's Building, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, UK., Atack JR; Main Building, Medicines Discovery Institute, Park Place, Cardiff University, Cardiff, CF10 3AT, UK., Paradowski M; Main Building, Medicines Discovery Institute, Park Place, Cardiff University, Cardiff, CF10 3AT, UK., Lambert JJ; Division of Cellular & Systems Medicine, School of Medicine, Medical Sciences Institute, Dundee University, Dow Street, Dundee DD1 5HL, UK.
Jazyk: angličtina
Zdroj: Biomolecules [Biomolecules] 2024 Apr 09; Vol. 14 (4). Date of Electronic Publication: 2024 Apr 09.
DOI: 10.3390/biom14040460
Abstrakt: 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 GABA A R 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) GABA A Rs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABA A Rs, 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.
Databáze: MEDLINE
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