CEREBRAL-CORTEX G(S)ALPHA PROTEIN-LEVELS AND FORSKOLIN-STIMULATED CYCLIC-AMP FORMATION ARE INCREASED IN BIPOLAR AFFECTIVE-DISORDER

Experimental animal and peripheral blood cell studies point to guanine nucleotide regulatory (G) protein disturbances in bipolar affective disorder. We have previously reported elevated prefrontal cortex G(s)alpha protein in bipolar affective disorder and have now extended these preliminary observations in a larger number of subjects, assessing the brain regional specificity of these changes in greater detail, determining the functional biochemical correlates of such changes, and evaluating their diagnostic specificity. Membrane G protein (G(s)alpha, G(i)alpha, G(o)alpha, and Gbeta) immunoreactivities were estimated by western blotting in postmortem brain regions obtained from 10 patients with a DSMIII-R diagnosis of bipolar affective disorder and 10 nonpsychiatric controls matched on the basis of age, postmortem delay, and brain pH. To examine whether there were functional correlates to the observed elevated G(s)a levels, basal and GTP(gamma)S- and forskolin-stimulated cyclic AMP production was determined in the same brain regions. Compared with controls, G(s)alpha (52-kDa species) immunoreactivity was significantly (p < 0.05) elevated in prefrontal (+36%), temporal (+65%), and occipital (+96%) cortex but not in hippocampus (+28%), thalamus (-23%), or cerebellum (+21%). In contrast, no significant differences were found in the other G protein subunits (G(i)alpha, G(o)alpha, G(beta)) measured in these regions. Forskolin-stimulated cyclic AMP production was significantly increased in temporal (+31%) and occipital (+96%) cortex but not in other regions. No significant differences were apparent in basal or GTPgammaS-stimulated cyclic AMP production. A significant correlation (r = 0.60, p < 0.001) was observed between forskolin-stimulated cyclic AMP formation and G(s)alpha (52 kDa) immunoreactivity when examined across these cortical regions. The observed increase in G(s)alpha may be specific to bipolar disorders as no significant differences were detected in G(s)alpha levels in temporal cortex from patients with either schizophrenia (n = 7) or Alzheimer's disease (n = 7). In summary, the present study confirms and extends our earlier findings and supports the notion that increased G(s)alpha levels and possibly G(s)alpha-adenylyl cyclase-mediated signal transduction are relevant to the pathophysiology of bipolar affective disorder.