Chronic lithium regulates the expression of adenylate cyclase and G_i-protein α subunit in rat cerebral cortex

A possible role for adenylate cyclase and guanine nucleotide-binding proteins (G proteins) in contributing to the chronic actions of lithium on brain function was investigated in rat cerebral cortex. It was found that chronic treatment of rats with lithium (with therapeutically relevant serum levels of ≈1 mM) increased levels of mRNA and protein for the calmodulin-sensitive (type 1) and calmodulin-insensitive (type 2) forms of adenylate cyclase and decreased levels of mRNA and protein for the inhibitory G-protein subunits G_iα1 and G_iα2. Chronic lithium did not alter levels of other G-protein subunits, including G_oα, G_sα, and Gβ. Lithium regulation of adenylate cyclase and G_iα was not seen in response to short-term lithium treatment (with final serum levels of ≈1 mM) or in response to chronic treatment at a lower dose of lithium (with serum levels of ≈0.5 mM). The results suggest that up-regulation of adenylate cyclase and down-regulation of G_iα could represent part of the molecular mechanism by which lithium alters brain function and exerts its clinical actions in the treatment of affective disorders.