Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: Therapeutic implications

In an attempt to find the key to reducing the excessive morbidity and morta lity seen with mood disorders, our laboratory has been extensively investig ating lithium's mechanisms of action in an integrated series of clinical an d preclinical studies. We have found that the chronic administration of the 2 structurally highly dissimilar agents, lithium and valproate, brings abo ut a strikingly similar reduction in protein kinase C (PKC) a and epsilon i sozymes in rat frontal colter and hippocampus. In view of PKC's critical ro le in regulating neuronal excitability and neurotransmitter release, we hav e postulated that PKC inhibition may have antimanic efficacy. In a small st udy, we have found that tamoxifen (which, in addition to its estrogen recep tor blockade, is also a PKC inhibitor) has marked antimanic efficacy. These exciting preliminary results suggest that PKC inhibitors may represent a n ovel class of improved therapeutic agents for bipolar disorder, and this is under further investigation. The beneficial effects of mood stabilizers re quire a lag period for onset of action and are generally not immediately re versed upon drug discontinuation; such patterns of effects suggest alterati ons 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 transcript ion factors and have found that both drugs increase AP-1 DNA binding activi ty 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-l-containing promoter, and mutations in the AP-I sites of the reporte r gene promoter markedly attenuate these effects. Both treatments also incr ease the expression of several endogenous proteins, whose genes are known t o be regulated by AP-I. 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 kina se 3 beta. We have also utilized mRNA reverse transcription-polymerase chai n reaction (RT-PCR) differential display to identify concordant changes in gene expression induced by the chronic administration of both lithium and v alproate. We have identified concordant changes in a number of cDNA bands b y both lithium and valproate. Cloning and characterizing of these genes is currently underway. The identification of the functions of these genes offe rs the potential not only for improved therapeutics for reducing the morbid ity and mortality associated with mood disorders, but may also provide impo rtant clues about the underlying pathophysiology.