Protein kinase C signaling in the brain: Molecular transduction of mood stabilization in the treatment of manic-depressive illness

Understanding the biology of the pharmacological stabilization of mood will undoubtedly serve to provide significant insight into the pathophysiology of manic-depressive illness (MDI). Accumulating evidence from our laborator ies and those of other researchers has identified the family of protein kin ase C isozymes as a shared target in the brain for the long-term action of both lithium and valproate. In rats chronically treated with lithium, there is a reduction in the hippocampus of the expression of two protein kinase isozymes, alpha and epsilon, as well as a reduction in the expression of a major PKC substrate, MARCKS, which has been implicated in long-term neuropl astic events in the developing and adult brain. In addition, we have been i nvesigating the down-stream impact of these mood stabilzizers on another ki nase system, GSK-3 beta and on the AP-1 family of transcription factors. Fu rther studies have generated promising preliminary data in support of the a ntimanic action of tamoxifen, and antiestrogen that is also a PKC inhibitor . Future studies must address the therapuetic relevance of these protein ta rgets in the brain using innovative strategies in both animal and clinical investigations to ultimately create opportunities for the discovery of the next generations of mood stabilizers for the treatment of MDI. Biol Psychia try 1999;46: 1328-1351 (C) 1999 Society of Biological Psychiatry.