The 5‐HT 4 Receptor

1 In the present study, the ability of the 5-hydroxytryptamine4 receptor (5-HT4 receptor) to modulate the release of 5-HT in the hippocampus of freely-moving rats was investigated by the in vivo microdialysis technique. 2 The 5-HT4 receptor agonist, renzapride (1.0-100 gIM, administered via the microdialysis probe) increased extracellular hippocampal levels of 5-HT in a concentration-dependent manner (approximately 200% maximal increase). The ability of renzapride (100 Mm, administered via the microdialysis probe) to elevate extracellular levels of 5-HT remained in the presence of the selective 5-HT reuptake blocker, paroxetine (1.0 gM, administered via the microdialysis probe). Furthermore, another 5-HT4 receptor agonist 5-methoxytryptamine (5-MeOT; 10 gM, administered via the microdialysis probe, in the presence of the non-5-HT4 5-HT receptor antagonists pindolol (10 gM) and methysergide (10 gM)) maximally elevated extracellular levels of 5-HT by approximately 450% in the rat hippocampus. The elevation of extracellular 5-HT levels induced by either renzapride (100 gM) or 5-MeOT (10 gM) was completely prevented by combined administration of the selective 5-HT4 receptor antagonist, GRI13808 (100 nM, administered via the microdialysis probe). GRI13808 (100 nM, administered via the microdialysis probe) administered alone, however, reduced extracellular hippocampal 5-HT levels by some 60%. In conclusion, the present study provides evidence that activation of the 5-HT4 receptor facilitates 5-HT release in the rat hippocampus in vivo.

Section: Resultsmentioning

confidence: 78%

5‐HT₄ receptor‐mediated modulation of 5‐HT release in the rat hippocampus in vivo

Jin

Barnes

1996

“…RS 67333 and RS 67506 acted as partial 5-HT4 receptor agonists in rat oesophagus; a property that appears to be true for most non-indole 5-HT4 receptor agonists (Table 3). This has been ascribed to the low receptor reserve associated with 5-HT4- mediated relaxant responses in this preparation (Ford & Clarke, 1993). Therefore, caution should be applied in interpreting the appearance (or lack thereof) of efficacy for RS 67333 and RS 67506, since their potency will be contingent upon the prevailing 5-HT4 receptor reserve.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

Eglen¹,

Bonhaus²,

Johnson³

et al. 1995

1 The pharmacology of two novel 5-HT4 receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxy phenyl)-3-[1(n-butyl)-4-piperidinyl]-1-propanone HCl) and RS 67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone HCl) have been assessed in vitro and in vivo.2 RS 67333 and RS 67506 exhibited affinities (pKi=8.7 and 8.8, respectively) for the 5-HT4 binding sites, labelled with [3H]-GR 113808, in guinea-pig striatum. The Hill coefficients from these displacement curves were not significantly different from unity. The compounds exhibited lower affinities (< 6.0) at several other receptors including 5-HTA, 5-HTID, 5-HT2A, 5-HT2c, dopamine D,, D2 and muscarinic M,-M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the a, (pKi=8.9 and 7.9, respectively) and Ca2 (pK,=8.0 and 7.3, respectively) binding sites. 3 At the 5-HT4 receptor mediating relaxation of the carbachol-precontracted oesophagus, RS 67333 and RS 67506 acted as potent (pECm 8.4 and 8.6, respectively), partial agonists (intrinsic activities, with respect to 5-HT were 0.5 and 0.6, respectively) with respect to 5-HT. Relaxant responses to RS 67333 or RS 67506 were surmountably antagonized by GR 113808 (10 nM), with apparent affinities (pKB) of 9.1 and 9.0, respectively. RS 67333 and RS 67506 induced dose-dependent increases in heart rate of the anaesthetized micropig (ED50 4.9 and 5.4 pg kg-',i.v.), with maximal increases of 35 and 47 beats min-', respectively. 4 RS 67333 and RS 67506, therefore, acted as potent, partial 5-HT4 receptor agonists in vitro and in vivo. These compounds, by virtue of their high potency and selectivity, may have some utility in elucidating the physiological role of 5-HT4 receptors.

“…This indicates that the facilitatory effect of 5-HT, at least at a concentration below 1 gM, is probably mediated by a 5-HT4 receptor (Ford & Clarke, 1993;Hoyer et al, 1994). The rank order of potency also correlates with their potency for the 5-HT4 receptor enhancing the peristaltic reflex in the guinea-pig isolated ileum (Costall et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

5‐HT₃ and 5‐HT₄ receptor‐mediated facilitation of the emptying phase of the peristaltic reflex in the marmoset isolated ileum

Tuladhar

Costall

Naylor

1996

1 The patterns of intestinal motility and the effect of an increase in intraluminal pressure were studied in vitro on segments obtained from the marmoset small intestine. 2 Segments obtained from the distal half of the marmoset small intestine exhibited segmentation, consisting of narrow annular contractions (lasting for 2-3 s) interposed between the relaxed segments of varying length. The subsequent contractions occurred slightly distal to the previous contraction, with ring-like contractions appearing to move in the aboral direction. Such segmentation was infrequent or absent in the segments obtained from the proximal half of the small intestine. An increase in intraluminal pressure inhibited segmentation and finally produced peristalsis in most of the tissues. 3 The influence of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on the threshold of the peristaltic reflex was investigated in the segments obtained from the distal half of the intestine after segmentation had subsided. The effect of drug application to the serosal surface was measured as a change in threshold pressure required to trigger the peristaltic reflex. A facilitation was defined in two ways (a) as a reduction in the threshold pressure required to trigger the reflex and (b) in those tissues that failed to respond with peristalsis on raising intraluminal pressure to the maximum attainable (1 kPa), as a reduction in threshold pressure compared to this value. 4 5-HT (7.85+0.19), 5-methoxytryptamine (7.79+0.24), 5-carboxamidotryptamine (6.66+0.13) and 2-methyl-5-HT (6.24+0.16) caused a concentration related facilitation of the peristaltic reflex, the pD2 values (mean+s.e.mean) being shown in parentheses. 5 The concentration-response curves to both 5-HT and 5-methoxytryptamine were dextrally shifted in a surmountable manner in the presence of GR 113808 (30 nM). pD2 values for 5-HT and 5-methoxytryptamine were significantly decreased to 6.98 + 0.24 and 6.83 + 0.36 respectively in the presence of GR 113808 (30 nM).6 In the presence of a high concentration of (10 jgM) 5-methoxytryptamine the subsequent addition of 2-methyl-5-HT (3-10 -OM) but not 5-methoxytryptamine (10 gM) facilitated peristalsis; the effect of 3 pM 2-methyl-5-HT was significantly decreased by 2 pM ondansetron. 7 It is concluded that the facilitation of the peristaltic reflex in the marmoset intestine induced by 5-HT at submicromolar concentrations involves a 5-HT4 receptor stimulation with an additional 5-HT3 receptor activation at higher concentrations.