SELECTIVE INCREASES IN PHOSPHOINOSITIDE SIGNALING ACTIVITY AND G-PROTEIN LEVELS IN POSTMORTEM BRAIN FROM SUBJECTS WITH SCHIZOPHRENIA OR ALCOHOL DEPENDENCE

Comparisons of the activity of the G protein-mediated phosphoinositide signal transduction system and of G protein levels were made in two r egions of frontal cortex from eight schizophrenic, alcohol-dependent, and control subjects, G protein-mediated phosphoinositide hydrolysis w as measured by stimulating cortical membranes incubated with [H-3]phos phatidylinositol with 0.3-10 mu M guanosine 5'-O-(3-thio) triphosphate (GTP gamma S). In frontal cortex areas 8/9, GTP gamma-induced phosphoi nositide hydrolysis was 50% greater in schizophrenic than control or a lcohol-dependent subjects, whereas there were no differences among the se groups of subjects in the response to GTP gamma S in frontal cortex area 10. Agonists for dopaminergic, cholinergic, purinergic, serotone rgic, histaminergic, and glutamatergic receptors coupled to the phosph oinositide signaling system increased [H-3]-phosphatidylinositol hydro lysis in a GTP gamma S-dependent manner, Responses to most agonists we re similar in all three subject groups in both cortical regions, with the largest difference being a 40% greater response to dopaminergic re ceptor stimulation in frontal cortex 8/9 from schizophrenic subjects, Measurements of the levels of phospholipase C-beta, and of alpha-subun its of G(q), G(o), G(i1), G(i2), and G(s), made by immunoblot analyses revealed no differences among the groups of subjects except for incre ased G alpha(o) in schizophrenic subjects and increased G alpha(o) and G alpha(i1) in alcohol-dependent subjects, These results demonstrate that schizophrenia is associated with increased activity of the phosph oinositide signal transduction system and increased levels of G alpha( o), whereas the phosphoinositide system was unaltered in alcohol depen dence, but G alpha(o) and G alpha(11) were increased.