To determine the possible physiological role of endogenous vasoactive intestinal peptide (VIP) in the control of cerebral somatostatin (SS), we studied the effect of endogenous VIP blockade on immunoreactive SS (IR-SS) accumulation by fetal rat cerebral cortical and hypothalamic cells in culture. Cells were cultured in minimum essential medium (MEM) with 10% fetal calf serum and 10% horse serum. After 7-10 days 'in vitro' media were replaced with MEMs without sera containing anti-VIP immunoglobulins G (IgG) for 1, 3, 6, 24 or 48 h. Controls received the same amount of IgG from normal rabbit serum (NRS). In another group of experiments, cells were incubated with VIP (10(-11) M to 10(-7) M) for 1, 3, 6 or 24 h. Exposure to anti-VIP IgG resulted in a decreased accumulation of IR-SS in both cerebral cortical and hypothalamic cells, whereas the addition of VIP caused a dose-dependent increase in total IR-SS, these effects being evident after 3 h incubation. The stimulatory action VIP on IR-SS was up to 129%, this being decreased to 86% by the addition of anti-VIP to plates containing 10(-7) M VIP. Patterns of IR-SS accumulation throughout prolonged incubation periods were qualitatively similar (in both cerebrocortical and hypothalamic cells) in the presence or absence of anti-VIP IgG. However, in plates containing anti-VIP, the total amount of IR-SS was lower than in the control groups (IgG from NRS). These findings demonstrate that, at this time of brain development, somatostatinergic neurons may be under the physiological regulation of locally produced VIP.