Increased alpha-subunit (alpha s) levels of both the 45- and 52-kDa isoforms of the stimulatory guanine nucleotide binding protein (G-protein), have been found in postmortem brain and mononuclear leukocytes from patients with bipolar disorder (BD). The pathophysiological mechanism responsible for increased alpha s protein levels is unknown, however, it may involve increased expression of the gene encoding this protein. To assess this possibility, alpha s mRNA levels were determined by RT-PCR in postmortem brain from 10 subjects with an antemortem diagnosis of BD and age- and sex-matched control subjects in whom we had previously reported increased alpha s protein levels. There were no significant differences in alpha s mRNA levels in frontal, temporal, or occipital cortex between BD and control subjects. Cerebral cortex alpha s mRNA levels did not correlate with age or postmortem interval. These findings do not support the notion that higher alpha s levels found in BD postmortem brain are a result of increased gene expression.