Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilizers.
BACKGROUND
New research is dramatically altering our understanding of the molecular mechanisms underlying neuronal communication.


OBJECTIVE
To elucidate the molecular mechanisms underlying the therapeutic effects of mood stabilizers.


METHODS
Results from integrated clinical and laboratory studies are reviewed.


RESULTS
Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) isozymes in rat frontal cortex and hippocampus. In a small study, tamoxifen (also a PKC inhibitor) had marked antimanic efficacy. Both lithium and valproate regulate the DNA binding activity of the activator protein I family of transcription factors. Using mRNA differential display, it was also shown that chronic administration of lithium and valproate modulates expression of several genes. An exciting finding is that of a robust elevation in the levels of the cytoprotective protein, bcl-2.


CONCLUSIONS
The results suggest that regulation of signalling pathways may play a major part in the long-term actions of mood stabilizers. Additionally, mood stabilizers may exert underappreciated neuroprotective effects.
Manji
H K
HK
Laboratory of Molecular Pathophysiology, Wayne State University School of Medicine, Detroit, Michigan, USA. manjih@intra.nimh.nih.gov
Moore
G J
GJ
Chen
G
G
D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects
D018692:Antimanic Agents; D014157:Transcription Factors; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3