Following the discovery of the growth hormone release-inhibiting factor somatostatin from extracts of ovine hypothalamus, an N-terminally extended somatostatin of 28 amino acids has been identified in mammalian tissue. The original peptide, somatostatin-14 (SS14), corresponds to the C-terminus of somatostatin-28 (SS28). Both SS28 and SS14 have biological activity, occur in several rat brain regions, are present in cell bodies and nerve terminals and can be released in vitro upon depolarization in a calcium-dependent manner. Further, high-affinity binding sites were described for SS14, which also bind SS28 (refs 20-23). Recently, a dodecapeptide which corresponds to the N-terminus of somatostatin-28, somatostatin-28(1-12), has been characterized in rat hypothalamus. Radioimmunological and immunohistochemical studies have indicated the presence of SS28(1-12)-like immunoreactivity in several cortical and subcortical regions of the rat brain. This peptide was found to be unevenly distributed with the highest concentration in the hypothalamus, and preferentially localized to dendritic and axonal processes and terminals. These observations suggest that SS28(1-12) may be a neurotransmitter. In this study, we describe a calcium-dependent release of a SS28(1-12)-like peptide from hypothalamic slices in vitro. This finding supports a neurotransmitter function for this peptide.