Guanine nucleotide binding proteins (G proteins) have been implicated in the pathophysiology of bipolar affective disorder. In the present investigation receptor‐mediated G protein activation and changes in G protein trimeric state were examined in frontal cortical membranes obtained from postmortem brains of bipolar affective disorder subjects and from age‐, sex‐, and postmortem interval‐matched controls. Stimulation of cortical membranes with serotonin, isoproterenol, or carbachol increased guanosine 5′‐O‐(3‐[35S]thiophosphate) ([35S]GTPγS) binding to specific Gα proteins in a receptor‐selective manner. The abilities of these receptor agonists to stimulate the binding of [35S]GTPγS to the Gα proteins was enhanced in membranes from bipolar brains. Immunoblot analyses showed increases in the levels of membrane 45‐ and 52‐kDa Gαs proteins but no changes in the amounts of Gαi, Gαo, Gαz, Gαq/11, or Gβ proteins in membrane or cytosol fractions of bipolar brain homogenates. Pertussis toxin (PTX)‐activated ADP‐ribosylations of Gαi and Gαo were enhanced by ∼80% in membranes from bipolar compared with control brains, suggesting an increase in the levels of the trimeric state of these G proteins in bipolar disorder. Serotonin‐induced, magnesium‐dependent reduction in PTX‐mediated ADP‐ribosylation of Gαi/Gαo in cortical membranes from bipolar brains was greater than that observed in controls, providing further evidence for enhanced receptor‐G protein coupling in bipolar brain membranes. In addition, the amounts of Gβ proteins that coimmunoprecipitated with the Gα proteins were also elevated in bipolar brains. The data show that in bipolar brain membrane there is enhanced receptor‐G protein coupling and an increase in the trimeric state of the G proteins. These changes may contribute to produce exaggerated transmembrane signaling and to the alterations in affect that characterize bipolar affective disorder.