Chronic treatment with the mood stabilizer lithium is required to generate its mood stabilizing effect in the treatment of bipolar disorder. Our recent studies have shown that chronic lithium treatment increases mRNA and protein levels of the cytosolic glutathione s-transferase (GST) M1 isoenzyme. Cytosolic GST encompasses a family of detoxification enzymes that include four main classes: alpha (A), mu (M), pi (P) and theta (T). The purpose of this study is to examine the effect of lithium on GST isoenzymes that are expressed in brain, and determine the role of GST in the neuroprotective effects of lithium against oxidative stress. We found in primary cultured rat cerebral cortical cells that chronic lithium treatment not only increased GST M1 mRNA levels, but also increased GST M3, M5 and A4 mRNA levels. Chronic lithium treatment increased GST enzyme activity when 1-chloro-2, 4-dinitrobenzene and 4-hydroxynonenal were used as substrates. In addition, we found that chronic lithium treatment inhibited reactive oxygen metabolite H(2)O(2)-induced cell death and DNA fragmentation in primary cultured rat cerebral cortical cells, while GST inhibitor ethacrynic acid reduced the neuroprotective effect of lithium against H(2)O(2)-induced cell death and DNA fragmentation. Since GST conjugates glutathione, the major antioxidant in brain, with a variety of oxidized products to form nontoxic products, and plays an important role in cellular protection against oxidative stress, our findings suggest that lithium selectively targets GST isoenzymes in order to produce neuroprotective effects against oxidative stress.