INCREASE IN [H-3] CAMP BINDING-SITES AND DECREASE IN G(I-ALPHA) AND G(O-ALPHA) IMMUNOREACTIVITIES IN LEFT TEMPORAL CORTICES FROM PATIENTS WITH SCHIZOPHRENIA

To search for possible alterations in second messenger systems in the temporal cortex (Brodmann's area 22) of patients with schizophrenia, we measured the binding activities of [H-3]adenosine 3',5'-cyclic monophosphate ([H-3]cAMP) and [H-3]4beta-phorbol 12,13-dibutyrate ([H-3]PDBu) which can label the regulatory subunit of cAMP-dependent protein kinase (protein kinase A) and the regulatory domain of Ca2+/phospholipid-dependent protein kinase (protein kinase C), respectively. We also immunoquantified the variable subunits of guanine nucleotide binding proteins (G-proteins), using specific polyclonal antisera against G(salpha), G(ialpha) and G(oalpha). Brains were obtained at autopsy on 10 patients with schizophrenia and 10 age-matched control subjects. Representative Scatchard plots for speCifiC [H-3]cAMP bindings to the soluble fraction consisted of a single component with high affinity (K(d) = 2.36 nM, B(max) = 737 fmol/mg protein). Among the tested adenyl and guanyl nucleotides, or neuroleptics, cAMP alone potently inhibited the binding (K(i) = 4.95 nM). The binding sites for [H-3]cAMP were discretely localized, and were in the order of: cerebral cortex = hypothalamus = amygdala > hippocampus = neostriatum = thalamus = nucleus accumbens > globus pallidus = cerebellum. Specific [H-3]cAMP bindings to the soluble fractions were about 30% greater in the left temporal cortices of schizophrenic patients, as compared to findings in the right side of the patients and the left side of the control subjects, no control brain showed this asymmetry. The specific [H-3]PDBu binding in schizophrenic and control groups did not change. G(ialpha) and G(oalpha) immunoreactivities in the crude membranes were decreased by about 30% in the left temporal cortices of schizophrenic patients, as compared to findings in the controls, on the left side, while G(salpha) immunoreactivities were unchanged between the two groups, on either side. Our findings suggest the enhanced responsiveness of adenylate cyclase to receptor stimulation through relative preponderance of G(salpha) over G(ialpha), which in turn would facilitate the generation of regulatory subunits of protein kinase A. The significance of decreased G(oalpha) immunoreactivities in schizophrenia is the subject of ongoing study. Our observations support the hypothesis of left ('dominant') temporal lobe dysfunction in schizophrenia.