EFFECTS OF CHRONIC LITHIUM AND CARBAMAZEPINE TREATMENT OF G-PROTEIN SUBUNIT EXPRESSION IN RAT CEREBRAL-CORTEX

Although lithium and carbamazepine (CBZ) are effective in the treatment of bipolar affective disorder, their mechanism of action is still unknown. Recent evidence suggests that lithium and CBZ might exert their therapeutic effects by modulating the function of guanosine triphosphate (GTP)-regulatory (G) proteins associated with central nervous system second messenger systems. In the present study, we showed that chronic lithium administration decreases Galpha(s), Galpha(i1), and Galpha(i2) messenger RNA (mRNA) abundance hy 25%-30% in rat cerebral cortex. However, the levels of Galpha(s), Galpha(i1), and Galpha(i2) mRNA were unaffected by chronic CBZ treatment. The effects of lithium on Galpha(s), Galpha(i1), and Galpha(i2) mRNA levels appear to be selective, as the mRNA levels of Galpha(o), Galpha(x), Gbeta1, Gbeta2, and Gbeta3 subunits remained unchanged. Two days after terminating chronic lithium treatment, changes in Galpha(s), Galpha(i1), and Galpha(i2) mRNA levels were not demonstrable. Short-term administration of lithium (2 days), however, reduced only the Galpha(i2) mRNA levels. Surprisingly, there was no significant difference in the amount of immunologically detectable Galpha(s-s), Galpha(s-1), Galpha(i(1+2)), Galpha(o), and Gbeta(1+2) in the cortex of rats chronically treated with lithium or CBZ, compared with controls. These data suggest that the effects of chronic lithium on Galpha(s), Galpha(i1), and Galpha(i2) mRNA levels are not shared by CBZ, although both treatments are known to be efficacious in bipolar affective disorder. Furthermore, the data suggest that lithium may modify G-protein functionality through the regulation of the genes expressing G-protein isoforms. However, this effect on G-protein expression appears complex and may be accompanied by compensatory posttranslational regulation of G-protein turnover.