The endozepine ODN stimulates [H-3]thymidine incorporation in cultured ratastrocytes

High concentrations of diazepam-binding inhibitor (DBI) mRNA have been dete cted in astrocytoma, suggesting that DBI-derived peptides may play a role i n glial cell proliferation. In the present study, we have investigated the effect of a processing product of DBI, the octadecaneuropeptide ODN, on DNA synthesis in cultured rat astrocytes. At very low concentrations (10(-14) to 10(-11) M), ODN caused a dose-dependent increase of [H-3]thymidine incor poration. At higher doses (10(-10) to 10(-5) M), the effect of ODN graduall y declined. The central-type benzodiazepine receptor antagonist flumazenil (10(-6) M) completely suppressed the stimulatory action of ODN whereas the peripheral-type benzodiazepine receptor ligand, PK11195 (10(-6) M) had no e ffect. The ODN-induced stimulation of [H-3]thymidine incorporation was mimi cked by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). T he GABA(A) receptor antagonist bicuculline (10(-4) M) suppressed the effect of both ODN and DMCM on DNA synthesis. Exposure of cultured astrocytes to the specific GABA(A) agonist 3APS (10(-10) to 10(-4) M) also induced a dose -related increase of [H-3]thymidine incorporation. The present study indica tes that ODN, acting through central-type benzodiazepine receptors associat ed with the GABA(A) receptor complex, stimulates DNA synthesis in rat glial cells. These data provide evidence for an autocrine role of endozepines in the control of glial cell proliferation. (C) 1999 Elsevier Science Ltd. Al l rights reserved.