Lithium's clinical utility in treating affective disorders is well established. However, the relevant pharmacological mechanism(s) for these actions of the ion have not been elucidated. Numerous previous reports have described the effects of lithium on various serotonergic and other neurotransmitter mechanisms. Recent investigations have suggested that the clinical effects of lithium may be mediated by the ion's ability to inhibit the dephosphorylation of inositol-1-phosphate and thus antagonize phosphatidylinositol hydrolysis which is a signal transduction system shared by various neurotransmitters and hormones. Investigations performed in our laboratory have documented the effect of lithium on brain serotonin release and on the role of protein kinase C (PKC) in modulating serotonin release. In preliminary studies, we have observed that lithium can inhibit (1) PKC-stimulated serotonin release in brain and platelets and (2) PKC stimulation induced translocation of the enzyme in brain and platelets. These studies also indicate that platelet PKC subcellular distribution and manic patients are markedly different from controls. In the proposed investigation, we plan to (1) examine platelet serotonin release and irs modulation by PKC stimulation in patients with affective disorders, (2) measure platelet protein kinase C activity, its subcellular distribution and its response to serotonergic and other stimuli in subjects diagnosed as having affective disorders, and (3) examine the relationship between clinical response to lithium and its effects on the above platelet serotonin and PKC markers. The studies aim to (1) explore the possibility that PKC is a biological marker for mania and (2) test the hypothesized relationship between lithium's therapeutic action in affective disorders and its effects on phosphorylation mediated by PKC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH045166-04
Application #
3384810
Study Section
Psychopathology and Clinical Biology Research Review Committee (PCB)
Project Start
1989-05-01
Project End
1994-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Wang, H Y; Johnson, G P; Friedman, E (2001) Lithium treatment inhibits protein kinase C translocation in rat brain cortex. Psychopharmacology (Berl) 158:80-6
Hahn, C G; Friedman, E (1999) Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord 1:81-6
Wang, H Y; Markowitz, P; Levinson, D et al. (1999) Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J Psychiatr Res 33:171-9
Wang, H Y; Friedman, E (1999) Effects of lithium on receptor-mediated activation of G proteins in rat brain cortical membranes. Neuropharmacology 38:403-14
Tilakaratne, N; Friedman, E (1996) Genomic responses to 5-HT1A or 5-HT2A/2C receptor activation is differentially regulated in four regions of rat brain. Eur J Pharmacol 307:211-7
Tilakaratne, N; Yang, Z; Friedman, E (1995) Chronic fluoxetine or desmethylimipramine treatment alters 5-HT2 receptor mediated c-fos gene expression. Eur J Pharmacol 290:263-6
Friedman, E; Hoau-Yan-Wang; Levinson, D et al. (1993) Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 33:520-5
Friedman, E; Butkerait, P; Wang, H Y (1993) Analysis of receptor-stimulated and basal guanine nucleotide binding to membrane G proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Anal Biochem 214:171-8
Wang, H Y; Eberle-Wang, K; Simansky, K J et al. (1993) Serotonin-induced muscle contraction in rat stomach fundus is mediated by a G alpha z-like guanine nucleotide binding protein. J Pharmacol Exp Ther 267:1002-11
Wang, H Y; Pisano, M R; Friedman, E (1992) Age-related alteration in G protein function in rat cortex. Ann N Y Acad Sci 663:426-8

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