Serotonin 5‐HT4 receptors are widely distributed in the periphery and in brain, where they modulate the release of various neurotransmitters and have been implicated in learning and memory. Nine C‐terminal splice variants of this receptor have been cloned in mammalian species. In the rat, three such variants have been described: 5‐HT4(a), 5‐HT4(b), and 5‐HT4(e). In the present study, we have examined several aspects of the distribution of these receptors in brain. First, we provide, in rat and guinea pig, a detailed comparison of the distribution of 5‐HT4 receptors labeled by the antagonist [125I]‐SB 207710 with the distribution of their encoding mRNA visualized by in situ hybridization histochemistry (ISHH). The results suggest that, in several projection systems (striato‐nigral and striato‐pallidal pathways, projection from dentate granule cells to field CA3, habenulo‐interpeduncular pathway), 5‐HT4 receptors are located both somatodendritically and axonally. Second, we have analyzed the distribution of mRNA for the three known rat splice variants by reverse transcription‐polymerase chain reaction (RT‐PCR) and by ISHH. RT‐PCR indicates that all three variants are widely distributed, with 5‐HT4(b) mRNA being present in all regions examined (olfactory tubercle, striatum, hippocampus, inferior colliculus, substantia nigra, parietal cortex) and 5‐HT4(a) and 5‐HT4(e) showing a somewhat more restricted distribution. In other regions (periaqueductal gray, reticular formation, medial septum, diagonal band), faint ISHH signals are observed for 5‐HT4(a)+4(e) mRNAs, whereas 5‐HT4(b) mRNA signals are almost undetectable. Finally, neurotoxic lesions of basal ganglia components in guinea pig also indicate a location of these receptors on terminals of striatal projection neurons. J. Comp. Neurol. 484:418–439, 2005. © 2005 Wiley‐Liss, Inc.
