POTENTIATION OF ASTROGLIAL NITRIC-OXIDE SYNTHASE TYPE-2 EXPRESSION BYLITHIUM-CHLORIDE

The mechanisms underlying the antimanic effects of lithium are largely unknown but may involve long-term changes in brain gene expression. T o determine if lithium could modify gene expression in astrocytes, the predominant cell type in brain, we tested the effects of LiCl on expr ession of nitric oxide synthase type 2 (NOS-2) in cultured glial cells . Incubation of primary rat astrocytes with endotoxin [lipopolysacchar ide (LPS)] and proinflammatory cytokines induced NOS-2 gene and protei n expression, as assessed by nitrite production and measurement of L-c itrulline synthesis in whole cell lysates. Incubation with LiCl, but n ot KCl, increased NOS-2 activity up to 1.6-fold. LiCl also potentiated (up to 2.7-fold) the induction of NOS-2 expression by LPS plus interf eron-gamma in C6 glioma cells but had little effect on LPS-induced nit rite accumulation from mouse RAW 264.7 macrophages. LiCl increased NOS -2 mRNA steady-state levels, suggesting an effect on mRNA stability an d/or NOS-2 gene transcription. These results demonstrate that LiCl can modify astroglial gene expression and suggest that chronic treatment with lithium could exacerbate inflammatory responses in brain glial ce lls.