Serotonin 5‐HT₄ receptors and their mRNAs in rat and guinea pig brain: Distribution and effects of neurotoxic lesions

Abstract

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.

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…This latter finding, coupled with autoradiographic results following selective lesions of either nigrostriatal DA neurons or cell bodies in the striatum, indicate that 5-HT4 receptors are not localized on DA terminals (Patel et al, 1995;Compan et al, 1996). Rather, they appear to have a somatodendritic localization within the striatum (Vilaro et al, 2005). 5-HT4 binding but not mRNA was also localized to the SN suggesting an axonal localization of the receptor on striatonigral projections (Vilaro et al, 2005).…”

“…Patel et al, 1995). A recent paper combining this approach with in situ immunohistochemistry found high levels of 5-HT4 binding sites and mRNA in the dorsal striatum and NA of the rat, guinea pig, and monkey (Vilaro et al, 2005). This latter finding, coupled with autoradiographic results following selective lesions of either nigrostriatal DA neurons or cell bodies in the striatum, indicate that 5-HT4 receptors are not localized on DA terminals (Patel et al, 1995;Compan et al, 1996).…”

“…Rather, they appear to have a somatodendritic localization within the striatum (Vilaro et al, 2005). 5-HT4 binding but not mRNA was also localized to the SN suggesting an axonal localization of the receptor on striatonigral projections (Vilaro et al, 2005). Very low densities were observed in neocortical regions including the frontal cortex.…”

“…At least 10 splice variants have been identified in 3 species: of these, the 5-HT4(a), 5-HT4(b), and 5-HT4 (e) have been described in the rat (Vilaro et al, 2005). Quantitative autoradiographic studies have shown that 5-HT4 receptors are dense in mesolimbic and nigrostriatal terminal regions as well as the SN (e.g.…”

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

“…Thus, ventromedial-to-dorsolateral-increasing gradients of labelling densities have been observed in the rat and mouse brain caudate-putamen (Waeber et al,428 1994; Vilaro et al, 1996), while it was less pronounced in the same structure of guinea pig brain; similarly, monkey and human caudate nuclei and putamens showed very high densities of receptor and mRNA binding sites but no apparent gradient in their distribution (Bonaventure et al, 2000;Vilaro et al, 2005). The decrease in binding densities following selective lesion of rat caudate-putamen indicated a somatodendritic localization of 5-HT 4 receptors on GABAergic projection neurons and cholinergic/GABAergic interneurons in this structure; on the other hand, following 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway, there were no changes in striatal levels of receptor binding, clearly indicating that this receptor was not localized on DAergic terminals (Compan et al, 1996;Vilaro et al, 2005). These data are in agreement with postmortem studies on brains of patients with Huntington's disease or PD, showing a decrease in receptor binding only in the first group of patients (Reynolds et al, 1995;Vilaro et al, 2005).…”