REGULATION OF SECOND MESSENGER SYSTEMS IN EBV-TRANSFORMED B-CELL LINES

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Schizophrenia is an idiopathic and probably heterogenous disorder. Evidence suggest that disturbances in the cyclic AMP second messenger system may contribute to the pathophysiology of schizophrenia. Studies using postmortem brain tissue have shown enhanced cAMP production in response to NaF, Gpp[NH]p and a D1 receptor agonist in schizophrenic patients as compared to normals (Science 221:1304, 1983). 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 the cyclic AMP second messenger system 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 beta-lymphocytes that have been transformed with the Epstein-Barr virus. In our group, Dr. Kulaga has transformed cells from twins discordant for schizophrenia, and from unrelated schizophrenic patients and normals. We feel that the availability of these cells offers an ideal opportunity for evaluating, under a controlled setting, the regulation of second messenger systems in schizophrenia patients. Initial studies are in process to evaluate compounds that regulate cyclic AMP accumulation in these transformed B cells. Cells were retreated 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. Forskolin, cholera toxin, PGE 1, PMA, dopamine and isoproterenol increased cyclic AMP accumulation in these cells. Pretreatment of the cells with PMA potentiated the cyclic AMP accumulation produced by forskolin, cholera toxin, pGE1, isoproterenol and dopamine. The effects of PMA were partially antagonized by staurosporin, an inhibitor of protein kinase C. These preliminary results indicate that the B cell lines are a useful model to study the regulation of cyclic AMP in human cells.