Disease relevance of Htr4

• The purpose of this investigation was to determine whether a nutritionally essential amino acid, l-lysine, acts like a serotonin receptor 4 (5-HT4) antagonist, and if l-lysine is beneficial in animal models of serotonin (5-HT)-induced anxiety, diarrhea, ileum contractions, and tachycardia and in stress-induced fecal excretion [1].
• Orally applied l-lysine (1 g/kg of body weight) inhibited (P < 0.12) diarrhea triggered by coadministration of restraint stress and 5-hydroxytryptophane (10 mg/kg of body weight), and significantly blocked anxiety induced by the 5-HT4 receptor agonist (3.0 mmol/liter) in rats in vivo [1].
• In addition, stereotaxic microinjections of herpes simplex viruses, transformed to overexpress 5-HT4 receptors, increase DRN 5-HT neuronal mean activity when performed in the medial prefrontal cortex (mPFC) but not in the striatum or in the hippocampus [2].
• 5-HT4 agents were unable to alter haloperidol's effects on striatal messenger RNA levels or catalepsy [3].
• In the TMM, relaxation of carbachol-induced contracture by 5-HT4 receptor agonism of longitudinal muscle was recorded [4].

Psychiatry related information on Htr4

• 5-HT4 receptors in the hippocampus modulate rat locomotor activity [5].
• Olfactory association learning was used to investigate the involvement of 5-HT4 receptors in learning and long-term memory [6].
• The highly selective 5-HT4 receptor antagonists, SB 204070A (0.001-0.1 mg/kg s.c., 30 min pretest) and SB 207266A (0.01, 1 and 10 mg/kg p.o., 1 hr pre-test), increased time spent in social interaction without affecting locomotor activity, in a rat 15 min social interaction test under high light, unfamiliar conditions [7].
• The present study was conducted to determine the effect of BIMU1, a mixed 5-HT4 agonist/5-HT3 antagonist on social olfactory recognition in rats, a behaviour test which has previously been shown to access short-term memory and to be sensitive to cholinergic drugs [8].
• This hypothesis has been confirmed by functional evidence and further supports the view that 5-HT4 drugs could improve cognitive functions in diseases with impaired cholinergic transmission (e.g., Alzheimer's disease) [9].

High impact information on Htr4

• No effects of l-lysine or the 5-HT4 receptor agonist on plasma corticosterone and heart rate were recorded. l-Lysine may be a partial 5-HT4 receptor antagonist and suppresses 5-HT4 receptor-mediated intestinal pathologies and anxiety in rats [1].
• L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats [1].
• 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons [10].
• Here we show that although induction of LTP is unaffected by either pharmacological activation or inhibition of 5-HT4, application of the 5-HT4 receptor agonist, RS67333, completely blocks learning-induced depotentiation of LTP in the hippocampal CA1 region of freely moving rats, suggesting a role for 5-HT4 receptors in behavioural metaplasticity [11].
• The effects of 5HT on ICJ transit were inhibited by the intraperitoneal (ip) infusion of atropine, the 5HT receptor antagonists, methysergide, ketanserin, zacopride, and the 5HT4 agonist, SC53116 [12].

Chemical compound and disease context of Htr4

• During the day hours (0700-1900, light on), the local infusion of either 5-HT4 agonist, 5-MeOT (100 microM) or mosapride (10 microM), but not in their lower concentrations, into the bilateral hippocampus significantly increased motor activity as compared with the baseline values or the control rats [5].
• In the anaesthetized, vagotomized micropig, SDZ 205,557 produced only a transient blockade of 5-HT4-mediated tachycardia [13].
• However, the 5-HT3 and 5-HT4 receptor antagonist, tropisetron, the 5-HT4 receptor antagonist, 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester (SDZ 205-557), and the 5-HT2A receptor antagonist, ketanserin, did not affect the p-chloroamphetamine-induced hyperglycemia [14].
• These results suggest that 5-methoxytryptamine-induced hyperglycemia is mediated by the peripheral 5-HT2A receptor, although it has a high affinity for the 5-HT4 receptor [15].
• Neither the 5-HT2A receptor antagonist ketanserin nor the 5-HT3/5-HT4 receptor antagonist (3-alpha-tropanyl)-1 H-indole-3-carboxylic acid ester (ICS 205-930) proved effective against mCPP-induced hyperglycemia [16].

Biological context of Htr4

• Frontocortical 5-HT4 receptors exert positive feedback on serotonergic activity: viral transfections, subacute and chronic treatments with 5-HT4 agonists [2].
• Compound 2f not only markedly enhanced gastric emptying but was also a potent agonist at the isolated rat oesophageal tunica muscularis mucosae, a preparation sensitive to 5-HT4 receptor stimulation, and enhanced the twitch response in the LMMP preparation [17].
• Synthesis and structure-activity relationships of potent and orally active 5-HT4 receptor antagonists: indazole and benzimidazolone derivatives [18].
• 5-HT4 receptor antagonist affinity was further increased by alkylation at N-1 of the aromatic heterocycle [18].
• 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 [19].

Anatomical context of Htr4

• To verify whether this procognitive action occurs via the activation of the cholinergic nucleus basalis magnocellularis (NBM)-cortical pathways, we examined the effects of RS67333, a selective partial agonist of the 5-HT4 receptor, on rat performance in a place recognition task upon local administration of the drug into the NBM area [20].
• BACKGROUND: We recently identified a facilitory control exerted by serotonin4 (5-HT4) receptors on the in vivo firing activity of dorsal raphe nucleus (DRN) serotonergic (5-HT) neurons [2].
• A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carboxamides was synthesized and evaluated for antagonist affinity at the 5-HT4 receptor in the rat esophagus [18].
• Lasting increase in serotonin 5-HT1A but not 5-HT4 receptor subtypes in the kindled rat dentate gyrus: dissociation from local presynaptic effects [21].
• They were evaluated using radioligand binding assays with [3H]GR 113808, a 5-HT4 receptor selective ligand, in the rat striatum and the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig [22].

Associations of Htr4 with chemical compounds

• Benzimidazole derivatives. 4. The recognition of the voluminous substituent attached to the basic amino group of 5-HT4 receptor antagonists [23].
• These increases remain stable when the compounds are administered continuously during 3 and 21 days; the effects of the 3-day treatment are blocked by the 5-HT4 receptor antagonist GR 125487 (1000 microg/kg, intravenous [i.v.]) [2].
• METHODS AND RESULTS: Here we show that the subacute intraperitoneal (IP) injection of the 5-HT4 receptor agonists prucalopride (2.5 mg/kg) and RS 67333 (1.5 mg/kg) 30 minutes before the beginning of recordings augment the mean firing rate of DRN neurons by 40% and 66%, respectively [2].
• Additional evidence for the involvement of cAMP in the signaling by 5-HT4 receptors was obtained using the general phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine [24].
• 8c is an antagonist equipotent to the 5-HT4 receptor antagonist SDZ 205-557 (1) [22].

Physical interactions of Htr4

• Most of the synthesized compounds exhibited moderate-to-very high affinity (in many cases subnanomolar) for the 5-HT4 binding site and no significant affinity for the 5-HT3 receptor [25].

Regulatory relationships of Htr4

• These data suggest that 5-HT4 receptor activation enhances the ability of 5-HT3 receptor activation to induce intestinal allodynia [26].

Other interactions of Htr4

• Enhanced [35S]GTPgammaS binding was not detected in the presence of 5-HT1F, 5-HT2, 5-HT4, and 5-HT7 receptor agonists [27].
• In conclusion, the stimulation of glucose transport by 5-HT in cardiomyocytes is not mediated by a 5-HT1, 5-HT2, 5-HT3 or 5-HT4 receptor, nor by an adrenergic or dopaminergic receptor, but is likely to occur through the degradation of by a monoamine oxidase and concomitant formation of H2O2 [28].
• 5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells [29].
• Our data indicate that 5-HT has significant ability to modulate membrane excitability in STN neurons; modulation is accomplished by decreasing potassium conductance by activating 5-HT4 and 5-HT2C receptors [30].
• The highest density of 5-HT4 receptors labeled with [3H]GR113808 was found in the olfactory tubercle, substantia nigra, ventral pallium and striatum of rat and guinea pig, and similar regions of pig-tail macaque monkey [31].

Analytical, diagnostic and therapeutic context of Htr4

• In the present study, the ability of 5-hydroxytryptamine-4 (5-HT4) receptors in the hippocampus to enhance locomotor activity in rats was investigated by local infusion via microdialysis probes [5].
• Quantitative autoradiography of 5-HT4 receptors in brains of three species using two structurally distinct radioligands, [3H]GR113808 and [3H]BIMU-1 [31].
• 5. Reverse transcriptase polymerase chain reaction with specific primers detected mRNA of the 5-HT2A receptor in rat atria and ventricles, while expression of the 5-HT4 receptor was confined to atria [32].
• The effect of BIMU1 was antagonized by intraperitoneal injection of GR 125487, a very selective and potent 5-HT4 antagonist [8].
• Localization of 5-HT4 receptor mRNA in rat brain by in situ hybridization histochemistry [33].

References