Schizophrenia is an idiopathic and likely heterogenous disorder. Evidence suggest that disturbances in the cyclic AMP second messenger system may contribute to the pathophysiology of schizophrenia. Memo et al. (Science 221:1304, 1983), using postmortem brain tissue, report enhanced cyclic AMP production in response to NaF, Gpp[NH]p and a D1 receptor agonist in schizophrenics as compared to normals. Similar changes have been reported in schizophrenic patients when cyclic AMP is evaluated in a readily accessible source of tissue, blood cells. Our interest in cyclic AMP second messenger systems relates to the fact that catecholaminergic neurons in the central nervous system produce their effects predominantly through activation of second messenger systems. The second messenger, cyclic AMP, is regulated intracellularly by dopamine (D1 , D2), norepinephrine (beta1 , alpha2) and epinephrine (beta1, beta2, alpha2). In order to study cyclic AMP production in schizophrenic patients as compared to controls, we have initiated studies using B-lymphocytes that have been transformed with the Epstein-Barr virus from twins discordant for schizophrenia, and from unrelated schizophrenics and normals. These cells offer an ideal opportunity for evaluating, in a controlled setting, the regulation of second messenger systems in schizophrenics. Cells were pretreated with and without the protein kinase C activator, PMA, followed by treatment with forskolin, cholera toxin, PGE1, isoproterenol and dopamine agonists. The cyclic AMP production in response to these agents was measured using RIA. PMA potentiated PGE1-, cholera toxin-, forskolin- and isoproterenol- stimulated cyclic AMP accumulation in EBV-transformed human B lymphocytes. Cyclic AMP accumulation in response to forskolin and cholera toxin in the presence of PMA is significantly greater in schizophrenics as compared to normals. These results indicate that B cell lines are a useful model for the study of regulation of cyclic AMP in human cells.
