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Single Ethanol Withdrawal Regulates Extrasynaptic δ-GABA A Receptors Via PKCδ Activation.
Alcohol (ethanol, EtOH) is one of the most widely abused drugs with profound effects on brain function and behavior. GABAA receptors (GABAA Rs) are one of the major targets for EtOH in the brain. Temporary plastic changes in GABAA 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 δ-GABAA R endocytosis is implicated in EtOH-induced GABAA R plasticity, but the mechanisms by which the relative abundance and localization of specific GABAA Rs are altered by EtOH exposure and withdrawal remain unclear. In this study, we investigated the mechanisms underlying rapid regulation of extrasynaptic δ-GABAA R by a single EtOH withdrawal in cultured rat hippocampal neurons. Thirty-minutes EtOH (60 mM) exposure increased extrasynaptic tonic current ( I tonic ) amplitude without affecting synaptic GABAA R function in neurons. In contrast, at 30 min after withdrawal, I tonic 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 I tonic amplitude and the tolerance to acute EtOH, as well as the reduction of GABAA R-δ subunit abundance induced by a single EtOH withdrawal. Moreover, EtOH withdrawal selectively increased PKCδ level, whereas PKCδ inhibition specifically rescued the EtOH-induced alterations in GABAA R-δ subunit level and δ-GABAA R function. Together, we provided strong evidence for the important roles of PKCδ in the rapid regulation of extrasynaptic δ-GABAA R induced by a single EtOH withdrawal.
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