Abstract | RATIONALE: OBJECTIVE: This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABA(A) receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABA(A) receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABA(A) receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABA(A) receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. CONCLUSION: The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABA(A) receptors provides many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.
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Authors | Chase Matthew Carver, Doodipala Samba Reddy |
Journal | Psychopharmacology
(Psychopharmacology (Berl))
Vol. 230
Issue 2
Pg. 151-88
(Nov 2013)
ISSN: 1432-2072 [Electronic] Germany |
PMID | 24071826
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)
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Chemical References |
- Neurotransmitter Agents
- Receptors, GABA-A
- Androstane-3,17-diol
- Desoxycorticosterone
- tetrahydrodeoxycorticosterone
- Pregnanolone
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Topics |
- Allosteric Regulation
(physiology)
- Androstane-3,17-diol
(metabolism)
- Animals
- Brain
(metabolism)
- Desoxycorticosterone
(analogs & derivatives, metabolism)
- Humans
- Nerve Net
(physiology)
- Neural Inhibition
- Neuronal Plasticity
(physiology)
- Neurotransmitter Agents
(metabolism)
- Pregnanolone
(metabolism)
- Receptors, GABA-A
(metabolism)
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