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Alcohol (EtOH) intoxication causes changes in the rodent brain γ -aminobutyric acid receptor (GABA A R) subunit composition and function, playing a crucial role in EtOH withdrawal symptoms and dependence. Building evidence indicates that withdrawal from acute EtOH and chronic intermittent EtOH (CIE) results in decreased EtOH-enhanced GABA A R δ subunit-containing extrasynaptic and EtOH-insensitive α 1 βγ 2 subtype synaptic GABA A Rs but increased synaptic α 4 βγ 2 subtype, and increased EtOH sensitivity of GABA A R miniature postsynaptic currents (mIPSCs) correlated with EtOH dependence. Here we demonstrate that after acute EtOH intoxication and CIE, upregulation of hippocampal α 4 βγ 2 subtypes, as well as increased cell-surface levels of GABA A R α 2 and γ 1 subunits, along with increased α 2 β 1 γ 1 GABA A R pentamers in hippocampal slices using cell-surface cross-linking, followed by Western blot and coimmunoprecipitation. One-dose and two-dose acute EtOH treatments produced temporal plastic changes in EtOH-induced anxiolysis or withdrawal anxiety, and the presence or absence of EtOH-sensitive synaptic currents correlated with cell surface peptide levels of both α 4 and γ 1(new α 2) subunits. CIE increased the abundance of novel mIPSC patterns differing in activation/deactivation kinetics, charge transfer, and sensitivity to EtOH. The different mIPSC patterns in CIE could be correlated with upregulated highly EtOH-sensitive α 2 βγ subtypes and EtOH-sensitive α 4 βγ 2 subtypes. Naïve α 4 subunit knockout mice express EtOH-sensitive mIPSCs in hippocampal slices, correlating with upregulated GABA A R α 2 (and not α 4) subunits. Consistent with α 2, β 1, and γ 1 subunits genetically linked to alcoholism in humans, our findings indicate that these new α 2-containing synaptic GABA A Rs could mediate the maintained anxiolytic response to EtOH in dependent individuals, rat or human, contributing to elevated EtOH consumption.

molecular pharmacology

<i>α</i>2 Subunit–Containing GABA<sub>A</sub>Receptor Subtypes Are Upregulated and Contribute to Alcohol-Induced Functional Plasticity in the Rat Hippocampus

α2 Subunit–Containing GABAAReceptor Subtypes Are Upregulated and Contribute to Alcohol-Induced Functional Plasticity in the Rat Hippocampus

α2 Subunit–Containing GABA_AReceptor Subtypes Are Upregulated and Contribute to Alcohol-Induced Functional Plasticity in the Rat Hippocampus