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.