Chronic lithium administration alters a prominent PKC substrate in rat hippocampus.
The therapeutic effect of lithium in the treatment of bipolar disorder exhibits a significant delay in the onset of action and a persistence of efficacy beyond abrupt discontinuation of treatment. Lithium is known to alter receptor-coupled phosphoinositide second messenger pathway in brain, resulting in indirect changes in an endogenous activator of protein kinase C (PKC). Such evidence has suggested that PKC may be involved in the mechanism of action of lithium in the brain. PKC represents a site wherein long-term regulatory changes in cell function occur through the phosphorylation of specific phosphoproteins involved in processes including neurotransmitter release and receptor activation. In studies of rats exposed to lithium, however, we have found no significant effects of chronic administration on the relative activity, subcellular distribution, or activation of PKC in hippocampus. We did find a major reduction in the in vitro PKC mediated phosphorylation of two major substrates, 83 kDa and 45 kDa, in hippocampus of rats exposed to chronic lithium and maintaining clinically relevant therapeutic levels in brain. Using immunoblot analysis we have identified a known myristoylated alanine-rich C kinase substrate (MARCKS) at 83 kDa. In vivo levels of MARCKS in hippocampus were found to be significantly reduced after chronic lithium exposure. These findings persist in animals withdrawn from lithium, but are not apparent following acute treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Lenox
R H
RH
University of Vermont College of Medicine, Department of Psychiatry, Burlington 05405.
Watson
D G
DG
Patel
J
J
Ellis
J
J
D000818:Animals; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D006624:Hippocampus / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008094:Lithium / Q000008:administration & dosage*; D008297:Male; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D047908:Intracellular Signaling Peptides and Proteins; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D011506:Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D008094:Lithium; D011493:Protein Kinase C