Pharmacological characterization of 5-hydroxytryptamine3 receptors in murine brain and ileum using the novel radioligand [3H]RS-42358-197: evidence for receptor heterogeneity.

Previous studies have demonstrated species-specific differences in 5-hydroxytryptamine3 (5-HT3) receptors, but unequivocal evidence of 5-HT3 receptor subtypes, within a species, has not yet been obtained. The purpose of the current study was to test for heterogeneity in 5-HT3 receptors in murine tissues. 5-HT3 receptors in membranes derived from brain cerebral cortex of CD-1, C57Bl/6, and Swiss Webster mice and ileum of CD-1 mice were labeled with the 5-HT3 receptor antagonist [3H]RS-42358-197. Structurally diverse competing ligands were then used to characterize the binding site. [3H]RS-42358-197 bound with similar affinity in each of the cortical tissues (mean KD = 0.14 nM; range, 0.06-0.32 nM) but bound with lower affinity in ileal tissue (2.5 nM). The density of sites labeled with [3H]RS-42358-197 ranged from 10.4 fmol/mg of protein in Swiss Webster mouse cortex to 44.2 fmol/mg of protein in Sprague-Dawley rat cortex. Displacing ligands produced a pharmacologic profile of the [3H]RS-42358-197 binding site consistent with it being a 5-HT3 receptor: (R)-YM060 > (S)-zacopride > (R)-zacopride > MDL 72222 > 2-methyl-5-HT. However, > or = 10-fold differences in the affinity of certain ligands were found when comparing 5-HT3 binding sites in membranes from cerebral cortex of the different strains of mice and when comparing 5-HT3 binding sites in brain and ileal membranes prepared from the CD-1 mouse strain.(ABSTRACT TRUNCATED AT 250 WORDS)