Vasoactive intestinal peptide increases acetylcholine synthesis by rat hippocampal slices

The purpose of this study was to determine whether vasoactive intestinal peptide (VIP) might have a presynaptic modulatory effect at cholinergic terminals in the rat hippocampal formation. The exposure of rat hippocampal slices to VIP increased [3H]acetylcholine ([3H]ACh) synthesis from the precursor [3H]choline when tissue was incubated in normal or in high K+ medium; the maximal effect was apparent at 10(-8) M VIP and 10(-7) M VIP, respectively. Also, 10(-7) M VIP increased the activity of choline acetyltransferase (ChAT) in a hippocampal homogenate system. The increased synthesis by hippocampal slices was not the result of a VIP-induced alteration in either the basal release of ACh or the uptake of choline via the high-affinity uptake system. The increase in ACh synthesis induced by VIP in hippocampal slices was not associated with either adenylate cyclase or protein kinase C second messenger systems. There was no correlation between the effect of VIP on cyclic AMP production with that on ACh synthesis; also, forskolin, an activator of adenylate cyclase that increased cyclic AMP production 3.5-fold, did not mimic the effect of VIP on ACh synthesis. Similarly, there was no effect of the protein kinase C activator, phorbol myristate acetate, on ACh synthesis in hippocampal slices. However, the effect of VIP to increase ACh synthesis was not evident in the absence of extracellular calcium, suggesting that the effect of VIP is mediated by a calcium-requiring mechanism. The results suggest that, in the rat hippocampus, VIP has a presynaptic action at cholinergic terminals that results in enhanced synthesis of ACh, possibly by an action that alters ChAT activity.