Secretin stimulates the accumulation of cyclic AMP (half maximally stimulating concentration: 10-20 nM) in cultured mouse brain cells mainly consisting of glioblasts. Vasoactive Various peptides are known to be common to the brain and the gastrointestinal tract and pancreas (1). Some of these peptides (e.g., substance P, somatostatin, enkephalin) have been shown to elicit specific behavioral changes or changes in specific neuron firing rates or patterns (for review see refs. 2-4). They are, therefore, hypothesized to act on neurons as neuromodulators or neurotransmitters. Some neurohormones are also known to act on glial cells by regulating the intracellular level of cyclic AMP (for review see ref. 5). The possibility had to be considered that this would not only hold for biogenic amines such as norepinephrine but also for peptide hormones. Therefore, we investigated the effects of peptide hormones on the accumulation of cyclic AMP in glial cell cultures derived from neonatal mouse brain. We report-here that somatostatin inhibits the basal and the hormone-induced accumulation of cyclic AMP in such primary cultures. Furthermore, we report that the gastrointestinal hormones secretin and vasoactive intestinal peptide (VIP) stimulate the accumulation of cyclic AMP in these cultures, probably via different types of receptors. Thus a possible role of peptide hormones in the function of glial cells is indicated. In addition, the results suggest that secretin or a closely related compound might exert regulatory influence in the brain. A preliminary report of some of these results has been presented at a conference (6).MATERIALS AND METHODS Materials. Dulbecco's modified Eagle's medium and fetal bovine serum (GIBCO) were from C. Roth, Karlsruhe, Federal Republic of Germany. A partially purified preparation of VIP (porcine) was kindly donated by V. Mutt, Stockholm, Sweden. Isolated somatostatin (cyclic; bovine) was from Beckman,