Specific receptors for pituitary adenylate cyclase-activating polypeptide (PACAP), a novel peptide with neuroregulatory and neurotrophic functions, have been identified recently in different brain regions, including the hippocampus. In this study, we examined the effects of PACAP-38 on the excitatory postsynaptic field potentials (fEPSPs) evoked at the Schaffer collateral-CA1 synapses. Brief bath application of PACAP-38 (0.05 nM) induced a long-lasting facilitation of the basal transmission. Enhancement of this response was occluded in part by previous high-frequency-induced long-term potentiation (LTP). PACAP-38 did not significantly alter the paired-pulse facilitation (PPF). PACAP-38 has been shown to have a presynaptic effect on the septohippocampal cholinergic terminals, which results in an increase in basal acetylcholine (ACh) release. To assess whether the PACAP-38 enhancement of CA1 synapses was related to the activation of the cholinergic system we examined the effect of this peptide in the presence of atropine, a muscarinic receptor antagonist. The enhancement of the fEPSPs by PACAP-38 was blocked by bath application of atropine. These results show that PACAP-38 induces facilitation of hippocampal synaptic transmission through activation of the cholinergic system via the muscarinic receptors.Pituitary adenylate cyclase-activating polypeptide (PACAP) is a new member of a neuropeptide family that includes vasoactive intestinal peptide (VIP), glucagon, secretin, and growth hormone, and whose members are thought to play an important role in neuronal function (Miyata et al. 1989; Arimura 1998). PACAP has been isolated from the ovine hypothalamus on the basis of its ability to stimulate adenylate cyclase in rat anterior pituitary cells (Miyata et al. 1989) and it is present in the central nervous system (CNS) and in a variety of peripheral tissues (Masuo et al. 1992;Arimura and Shioda 1995;Shioda et al. 1997). Two distinct forms of this neuropeptide, PACAP-38 and PACAP-27, with 38 or 27 amino acids, respectively, have been characterized (Arimura and Shioda 1995). PACAP-38 and PACAP-27 possess similar biological activity (Miyata et al. 1990). PACAP-38 is the prevailing form in mammalian tissues (Arimura 1992). The amino-acid sequence of PACAP-38 is well-preserved in different species and is identical in sheep, rats, and humans (Arimura 1992). Two types of high-affinity PACAP receptors have been identified: The PACAP type-I receptor (PACAPRI), which specifically binds PACAP-38 and PACAP-27 with higher affinity than it binds VIP; and the PACAP type-II receptor (PACAPRII), which has high homology with the VIP receptor and binds PACAP-38, PACAP-27, and VIP with the same high affinity (Arimura 1992;Sokolov and Kleschevnikov 1995). PACAPRI is mainly distributed in the CNS, including the septum, hippocampus, cerebellar cortex, amygdala, nucleus accumbens, hypothalamus, and the entorhinal cortices (Masuo et al. 1992(Masuo et al. ,1993 and it is positively coupled to adenylate cyclase and phospholipase C, whereas PACA...