The function of the phosphoinositide second messenger system was assessed in occipital, temporal, and frontal cortex obtained postmortem from subjects with bipolar affective disorder and matched controls by measuring the hydrolysis of [3H]phosphatidylinositol ([3H]PI) incubated with membrane preparations and several different stimulatory agents. Phospholipase C activity, measured in the presence of 0.1 mM Ca2+ to stimulate the enzyme, was not different in bipolar and control samples. G proteins coupled to phospholipase C were concentration-dependently activated by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) and by NaF. GTP gamma S-stimulated [3H]Pl hydrolysis was markedly lower (50%) at all tested concentrations (0.3-10 microM GTP gamma S) in occipital cortical membranes from bipolar compared with control subjects. Responses to GTP gamma S in temporal and frontal cortical membranes were similar in bipolars and controls, as were responses to NaF in all three regions. Brain lithium concentrations correlated directly with GTP gamma S-stimulated [3H]Pl hydrolysis in bipolar occipital, but not temporal or frontal, cortex. Carbachol, histamine, trans-1-aminocyclopentyl-1,3-dicarboxylic acid, serotonin, and ATP each activated [3H]Pl hydrolysis above that obtained with GTP gamma S alone, and these responses were similar in bipolars and controls except for deficits in the responses to carbachol and serotonin in the occipital cortex, which were equivalent to the deficit detected with GTP gamma S alone. Thus, among the three cortical regions examined there was a selective impairment in G protein-stimulated [3H]Pl hydrolysis in occipital cortical membranes from bipolar compared with control subjects. These results directly demonstrate decreased activity of the phosphoinositide signal transduction system in specific brain regions in bipolar affective disorder.