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Single Ethanol Withdrawal Regulates Extrasynaptic δ-GABAA Receptors Via PKCδ Activation.
- Source :
- Frontiers in Molecular Neuroscience; 4/26/2018, p1-N.PAG, 14p
- Publication Year :
- 2018
-
Abstract
- Alcohol (ethanol, EtOH) is one of the most widely abused drugs with profound effects on brain function and behavior. GABA<subscript>A</subscript> receptors (GABA<subscript>A</subscript>Rs) are one of the major targets for EtOH in the brain. Temporary plastic changes in GABA<subscript>A</subscript>Rs after withdrawal from a single EtOH exposure occur both in vivo and in vitro, which may be the basis for chronic EtOH addiction, tolerance and withdrawal symptoms. Extrasynaptic d-GABA<subscript>A</subscript>R endocytosis is implicated in EtOH-induced GABA<subscript>A</subscript>R plasticity, but the mechanisms by which the relative abundance and localization of specific GABA<subscript>A</subscript>Rs are altered by EtOH exposure and withdrawal remain unclear. In this study, we investigated the mechanisms underlying rapid regulation of extrasynaptic d-GABA<subscript>A</subscript>R by a single EtOH withdrawal in cultured rat hippocampal neurons. Thirty-minutes EtOH (60 mM) exposure increased extrasynaptic tonic current (Itonic) amplitude without affecting synaptic GABA<subscript>A</subscript>R function in neurons. In contrast, at 30 min after withdrawal, Itonic amplitude and responsiveness to acute EtOH were both reduced. Similar results occurred in neurons with okadaic acid (OA) or phorbol 12,13-dibutyrate (PDBu) exposure. Protein kinase C (PKC) inhibition prevented the reduction of Itonic amplitude and the tolerance to acute EtOH, as well as the reduction of GABA<subscript>A</subscript>R-δ subunit abundance induced by a single EtOH withdrawal. Moreover, EtOH withdrawal selectively increased PKCd level, whereas PKCd inhibition specifically rescued the EtOH-induced alterations in GABA<subscript>A</subscript>R-δ subunit level and δ-GABA<subscript>A</subscript>R function. Together, we provided strong evidence for the important roles of PKCd in the rapid regulation of extrasynaptic d-GABA<subscript>A</subscript>R induced by a single EtOH withdrawal. [ABSTRACT FROM AUTHOR]
- Subjects :
- GABA receptors
ALCOHOL withdrawal syndrome
BRAIN function localization
Subjects
Details
- Language :
- English
- ISSN :
- 16625099
- Database :
- Complementary Index
- Journal :
- Frontiers in Molecular Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 129378710
- Full Text :
- https://doi.org/10.3389/fnmol.2018.00141