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NEUROPHARMACOLOGY

Differential Effects of Systemic Ethanol Administration on Protein Kinase C, , and Isoform Expression, Membrane Translocation, and Target Phosphorylation: Reversal by Chronic Ethanol Exposure

Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Systemic ethanol administration alters protein kinase C (PKC) activity in brain, but the effects of ethanol on the expression and translocation of specific isoforms are unknown. Rats were administered ethanol (2 g/kg i.p.) or saline and PKC levels were measured in the cytosolic and membrane fractions by Western blot analysis. PKC expression was increased in the cytosol and decreased in the membrane (P2) fraction of cerebral cortex at 10 min. At 60 min, expression of PKC in the P2 fraction was increased by 42.2 ± 12%, but cytosolic levels were unchanged. In contrast, PKC in the P2 fraction was decreased 32.7 ± 7% at 60 min but not at 10 min post-ethanol administration. PKC levels in the cytosol were reduced at 10 min post-ethanol administration and unchanged at 60 min. PKC expression was increased 36 ± 10 and 144 ± 52% in the P2 fraction both at 10 and 60 min post-ethanol administration, whereas cytosolic levels were unchanged. Serine phosphorylation of GABA_A receptor -chain was reduced, and phosphorylation of N-methyl-D-aspartate receptor NR1 subunit was increased 60 min following ethanol administration. There was no effect of acute ethanol administration on PKC isoform levels in the hippocampus. Ethanol challenge did not alter PKC isoform expression in the P2 fraction of cerebral cortex following chronic ethanol administration. These findings suggest that acute ethanol administration alters PKC synthesis and translocation in an isoform and brain region specific manner that leads to alterations in serine phosphorylation of receptors. Furthermore, chronic ethanol administration prevents ethanol-induced alterations in PKC expression in the P2 fraction, where PKC interacts with ethanol-responsive ion channels.

Address correspondence to: Dr. A. Leslie Morrow, Center for Alcohol Studies, CB7178, University of North Carolina, Chapel Hill, NC 27599-7178. E-mail: morrow{at}med.unc.edu