In an attempt to find the key to reducing the excessive morbidity and mortality seen with
mood disorders, our laboratory has been extensively investigating
lithium's mechanisms of action in an integrated series of clinical and preclinical studies. We have found that the chronic administration of the 2 structurally highly dissimilar agents,
lithium and
valproate, brings about a strikingly similar reduction in
protein kinase C (PKC) alpha and epsilon
isozymes in rat frontal cortex and hippocampus. In view of PKC's critical role in regulating neuronal excitability and
neurotransmitter release, we have postulated that PKC inhibition may have antimanic efficacy. In a small study, we have found that
tamoxifen (which, in addition to its
estrogen receptor blockade, is also a PKC inhibitor) has marked antimanic efficacy. These exciting preliminary results suggest that PKC inhibitors may represent a novel class of improved therapeutic agents for
bipolar disorder, and this is under further investigation. The beneficial effects of mood stabilizers require a lag period for onset of action and are generally not immediately reversed upon
drug discontinuation; such patterns of effects suggest alterations at the genomic level. We have therefore undertaken a series of studies to investigate the effects of these agents on the
AP-1 family of
transcription factors and have found that both drugs increase
AP-1 DNA binding activity in areas of rodent brain ex vivo and in human neuronal cells in culture. Both treatments also increase the expression of a reporter gene driven by an AP-1-containing promoter, and mutations in the
AP-1 sites of the reporter gene promoter markedly attenuate these effects. Both treatments also increase the expression of several endogenous
proteins, whose genes are known to be regulated by
AP-1. Although the precise mechanisms have not been fully elucidated, preliminary results suggest that these effects may be mediated, in part, by
mitogen-activating
protein kinases and
glycogen synthase kinase 3beta. We have also utilized
mRNA reverse transcription-polymerase chain reaction (RT-PCR) differential display to identify concordant changes in gene expression induced by the chronic administration of both
lithium and
valproate. We have identified concordant changes in a number of
cDNA bands by both
lithium and
valproate. Cloning and characterizing of these genes is currently underway. The identification of the functions of these genes offers the potential not only for improved
therapeutics for reducing the morbidity and mortality associated with
mood disorders, but may also provide important clues about the underlying pathophysiology.