The gene expression profile in rat brain was examined using microarrays in rats fed lithium chloride for 7 days (subacute) or 42 days (chronic). Brain lithium concentrations were 0.39 mM and 0.79 mM (therapeutically relevant), at 7 and 42 days, respectively. Of the 4132 genes represented in the microarrays, 25 genes were downregulated by at least twofold and none was upregulated after 7 days of treatment. Expression of 50 genes was downregulated by at least two-fold at 42 days, without any being upregulated. Lithium treatment for 7 days did not affect at a measurable extent expression of 37 of the 50 genes that were downregulated at 42 days. Genes whose expression was changed at 42 days coded for a number of receptors, protein kinases, transcription and translation factors, markers of energy metabolism, and signal transduction. Thus, chronic lithium at a therapeutically relevant concentration reduced expression of a large number of genes involved in multiple signaling and other pathways, without increasing expression at a comparable extent.