title: Ethanol-induced GABAA receptor alpha4 subunit plasticity involves phosphorylation and neuroactive steroids.
abstract: GABAA receptors containing α4 subunits are widely implicated in acute ethanol sensitivity, and their spatial and temporal regulation prominently contributes to ethanol-induced neuroplasticity in hippocampus and cortex. However, it is unknown if α4-containing GABAA receptors in the thalamus, an area of high α4 expression, display similar regulatory patterns following ethanol administration, and if so, by which molecular mechanisms. In the current study, thalamic GABAA receptor α4 subunit levels were increased following a 6-week-, but not a 2-week chronic ethanol diet. Following acute high-dose ethanol administration, thalamic GABAA receptor α4 subunit levels were regulated in a temporal fashion, as a decrease was observed at 2h followed by a delayed transient increase. PKCγ and PKCδ levels paralleled α4 temporal expression patterns following ethanol exposure. Initial decreases in α4 subunit expression were associated with reduced serine phosphorylation. Delayed increases in expression were not associated with a change in phosphorylation state, but were prevented by inhibiting neuroactive steroid production with the 5α-reductase inhibitor finasteride. Overall, these studies indicate that thalamic GABAA receptor α4 subunit expression following acute and chronic ethanol administration exhibits similar regulatory patterns as other regions and that transient expression patterns following acute exposure in vivo are likely dependent on both subunit phosphorylation state and neuroactive steroids.
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA; Department of Psychology, Center for Development and Behavioral Neuroscience, Binghamton University - State University of New York, Binghamton, NY 13902, USA. Electronic address: dwerner@binghamton.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: Werner
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA; Neuroscience Institute, National Research Council of Italy (CNR), Cagliari, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Porcu
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Boyd
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA.
authors.forename: Todd K
authors.initials: TK
authors.lastname: O'Buckley
authors.affiliation: Department of Psychology, Center for Development and Behavioral Neuroscience, Binghamton University - State University of New York, Binghamton, NY 13902, USA.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Carter
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7178, USA.
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
mesh_terms: D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D000431:Ethanol; D018120:Finasteride; C087857:protein kinase C gamma; D011493:Protein Kinase C; D051745:Protein Kinase C-delta
keywords: Alpha4 subunit; Ethanol; GABA receptors; Neuroactive steroids; PKC; Thalamus