We have investigated whether lithium has effects on transcription factor binding to consensus DNA sequences of AP-1 and cyclic AMP-responsive element (CRE) in cultured rat neurons and in vivo. Treatment of rat cerebellar granule cells (CGC) with lithium chloride induced a concentration-dependent increase in AP-1 and CRE binding activities with maximal effects at therapeutically relevant concentrations of 0.5 and 1.0 mM. Time-course studies show that lithium's effects on AP-1 and CRE binding were biphasic within the first 24 h of treatment in immature CGC in culture and persistent in mature CGC, lasting as long as 7 days. These actions were concurrent with an increase in the mRNA levels of c-fos and c-jun, as well as the protein levels of c-Fos, c-Jun, and phosphorylated CRE binding protein (p-CREB). Gel supershift assays using transcription factor-specific antibodies revealed that p-CREB, Jun D, and a Fos family protein(s) are components of the AP-1 binding complex in untreated and lithium-treated CGC. Chronic dietary treatment of rats with lithium carbonate for 4 weeks also significantly increased AP-1 and CRE binding activity in the frontal cortex, hippocampus, amygdala, and cerebellum. Similar to the results obtained in CGC, p-CREB, Jun D, and Fos family proteins are present in the AP-1 binding sites in the frontal cortex and hippocampus of untreated and lithium-treated rats. Lithium-induced activation of transcription factor binding to AP-1 and CRE sites in vivo and in vitro provides a new avenue to study the mechanisms of action of lithium in the treatment of manic depressive illness.