LONG-TERM ACTION OF LITHIUM - A ROLE FOR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL FACTORS REGULATED BY PROTEIN-KINASE-C

Lithium, a simple monovalent cation, represents one of psychiatry's mo st important treatments and is the most effective treatment for reduci ng both the frequency and severity of recurrent affective episodes. De spite extensive research, the underlying biologic basis for the therap eutic efficacy this drug remains unknown, and inrecent years, research has focused on signal transduction pathways to explain lithium's effi cacy in treating both poles of manic-depressive illness. Critical to a ttributions of therapeutic relevance to any observed biochemical effec t, however, is the observation that the characteristic prophylactic ac tion of lithium in stabilizing the profound mood cycling of bipolar di sorder requires a lag period for onset and is not immediately reversed upon discontinuation of treatment. Biochemical changes requiring such prolonged administration of a drug suggest alterations at the genomic level but, until recently, little has been known about the transcript ional and posttranscriptional factors regulated by chronic drug treatm ent, although long-term changes in neuronal synaptic function are know n to be dependent upon the selective regulation of gene expression. In this paper, we will present evidence to show that chronic lithium exe rts significant transcriptional and posttranscriptional effects, and t hat these actions of lithium may be mediated via protein kinase C (PKC )-induced alterations in nuclear transcription regulatory factors resp onsible for modulating the expression of proteins involved in long-ter m neural plasticity and cellular response. Such target sites for chron ic lithium may help unravel the processes by which a simple monovalent cation can produce a long-term stabilization of mood in individuals v ulnerable to bipolar illness. (C) 1994 Wiley-Liss, Inc.