DIFFERENTIAL-EFFECTS OF MOOD STABILIZERS ON FOS JUN PROTEINS AND AP-1DNA-BINDING ACTIVITY IN HUMAN NEUROBLASTOMA SH-SY5Y CELLS/

Lithium and sodium valproate (VPA) are effective in the treatment of b ipolar disorder (BD) and may function through the regulation of signal transduction pathways and transcription factors such as c-fos and c-J un, which in turn results to changes in gene expression. The long-term efficacy of lithium and VPA in ED suggests that the regulation of gen e expression may be an important target for these drugs. Preliminary e vidence suggests that c-fos levels and AP-1 binding may be regulated b y lithium and VPA, but the results are inconclusive. In the present st udy, we report differential effects of the two most commonly prescribe d mood stabilizers used to treat ED on Fos/Jun protein levels and thei r AP-1 binding activity in human neuroblastoma SH-SY5Y cells. At thera peutically relevant concentrations, both drugs acutely (< 24 h) induce d c-Fos immunoreactivity and AP-1 binding. In contrast to lithium, chr onic (1 week) treatment with VPA led to continued induction of c-Fos, in addition to induction of c-Jun immunoreactivity and a 33-35 kDa ban d previously identified as chronic FRA. AP-1 DNA binding activity was also increased after 1 week VPA treatment. These findings suggest that both these mood stabilizers may have-an effect on neuronal gene expre ssion of target genes containing the AP-1 consensus sequence in their promoter regions after acute treatment. The present results confirm an d extend previous findings on the regulation of c-fos expression and A P-1 binding after administration of mood stabilizers, and further eluc idate the mechanisms through which VPA increases AP-1 DNA binding. (C) 1998 Elsevier Science B.V. All rights reserved.