AbstractDistribution, chemical‐neuroanatomy, concentration, and uptake‐release properties of histamine (HA)‐containing neurons and the possible physiological effects of HA in the central and peripheral nervous system of the pulmonate snails,Helix pomatiaandLymnaea stagnalis, are described. In the CNS of both species, the distribution pattern of HA‐immunoreactive (HA‐IR) neurons was similar. In both species the majority were located in the buccal, cerebral, and pedal ganglia. InHelix, ∼400 HA‐IR neurons were seen, whereas inLymnaea∼130 labeled cells were visualized. The neuropils, connectives, commissures, several peripheral nerves, and a part of the peripheral tissues (lip and foot of both species and the upper tentacles ofHelix) were innervated by HA‐IR elements. Numerous sensory cells were found in the tentacles, lip, and statocysts. The HA concentration values assayed by HPLC ranged from 4.8 to 47.4 pmol/mg in the different central ganglia ofHelix, and from 4.3 to 18.6 pmol/mg inLymnaeaCNS, whereas the peripheral tissues contained 0.33–1 pmol/mg HA inHelixand 0.26–0.46 pmol/mg inLymnaea. In theLymnaeaCNS, a high‐affinity (37.6 μM), single component3H‐HA uptake system was demonstrated.3H‐HA release evoked by either electrical stimulation or 100 mM K+could be prevented in Ca2+‐free physiological solution. Voltage‐clamp experiments indicated specific changes caused by HA in the membrane conductance of identified central neurons ofHelixandLymnaea. Exogenously applied 10‐5M HA resulted in the acceleration of locomotion (gliding by foot cilia) ofLymnaea. The findings suggest an important signaling role of HA, described here for the first time, in the nervous system of higher‐order, pulmonate, gastropods, involving efferent, integrative, and sensory functions. The data can also be applied as a background for further specification of HA in the regulation of different behaviors in these species. J. Comp. Neurol. 475:391–405, 2004. © 2004 Wiley‐Liss, Inc.