5-HT3 receptors

Cytotoxics also cause cellular damage and the release of serotonin and other mediators from enterochromaffin cells. There is conflicting evidence regarding whether 5-HT3 receptors in the medulla are activated also during chemotherapy and contribute to production of emesis. Currently, the weight of evidence favours peripheral 5-HT3 receptors, with minor involvement of central receptors. 

Release of SP from neurons in the AP, NTS and dorsal vagal motor nucleus may play a role in vomiting induced by cytotoxics. Based on the relative effectiveness of selective antagonists of 5-HT3 receptors and NKi receptors against acute and delayed phases of cisplatin-induced vomiting, it has been suggested that serotonin has a greater role in the acute phase whereas SP has the major role in the delayed phase. 

Enterochromaffin cells are interspersed with mucosal cells mainly in the stomach and small intestine. In the blood, serotonin is present at high concentrations in platelets, which take up serotonin from the plasma by an active transport process. Serotonin is released on platelet activation. In the central nervous system, serotonin serves as a transmitter. The main serotonin-containing neurons are those clustered in form of the Raphe nuclei. Serotonin exerts its biological effects through the activation of specific receptors. Most of them are G-protein coupled receptors (GPCRs) and belong to the 5-HTr, 5-HT2-, 5-HT4-, 5-HTs-, 5-HT6-, 5-HT7-receptor subfamilies. The 5-HT3-receptor is a ligand-operated ion channel. 

HT3 receptors belong to the ligand-gated ion channel receptor superfamily, similar to the nicotinic acetylcholine or GABAa receptors and share elec-trophysiological and structural patterns. The receptors... 

The AMPA receptors for glutamate, the nicotinic acetylcholine receptor and the 5-HT3-receptor for serotonin are cation channels (Table 1). When they open, the major consequence is a sudden entry of Na+, depolarization and an excitatory postsynaptic potential (EPSP Fig. 1). 

Ethanol acts at 5-HTjg, 5-HT2C, and 5-HT3 receptors (Krystal et al. 2003b). Animal studies have shown that reduction of ethanol consumption is dependent on the presence of the 5-HT3 receptor (Hodge et al. 2004), a... 

Arch Gen Psychiatry 42 1050-1055, 1985 Hodge CW, Kelley SP, Bratt AM, et al 5-HT3 receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking. Neuropsychopharmacology 29 1807-1813, 2004... 

Similar to alcohol (Lovinger and White 1991) and volatile anesthetics (Machu and Harris 1994), trichoroethane, trichloroethylene, and toluene enhance 5-HT3 receptor function. All three inhalants significantly and reversibly potentiated, in a dose-dependent manner, 5-HT-activated currents, mediated by mouse 5-HT3 receptors expressed in Xenopus oocytes. Another feature common to these drugs is that the acute use of inhalants, as well as alcohol and volatile anesthetics, can produce nausea and vomiting (Meredith et al. 1989). It is believed that 5-HT3 receptors located in the area postrema mediate this action of alcohol and the volatile anesthetics (Aapro 1991). 

Aapro MS 5-HT3 receptor antagonists an overview of their present status and future potential in cancer therapy-induced emesis. Drugs 42 551-568, 1991... 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

HT3 receptor. 5-Hydroxytryptamine receptor a receptor for serotonin (a neurotransmitter), which activates a variety of second messenger signaling systems and through them indirectly regulates the function of ion channels. 

HT3 receptors are an exception to the general nomenclature of numbering subunits and denoting stoichiometry by subscripts. The 5-HT3 receptor subtype is denoted by the subscript 3 and the two known subunits are referred to as A and B . When expressed alone, 5-HT3-A subunits form functional homomeric receptors but these have a much smaller single channel conductance (less than 1.0 pS) and altered pharmacology compared to native 5-HT3 receptors. Native 5-HT3 receptors are likely to be pentameric heteromers of 5-HT3-A and 5-HT3-B subunits. 5-HT3-B subunits, unlike 5-HT3-A subunits, do not form functional receptors when expressed alone but when co-expressed with 5-HT3-A subunits, the receptors formed have functional properties similar to native 5-HT3 receptors. Synaptic transmission mediated by 5-HT3 receptors has been... 

The 5-HT3 receptor is found appropriately in mesocortical areas and while behavioural studies with their antagonists in rodents showed potential antipsychotic activity, they have proved ineffective in patients. 5-HTia agonists may be more useful. They have been found to increase the extracellular concentration of DA in the frontal cortex of rats but diminish apomorphine-induced stereotypy (striatal effect). So they could be of some benefit, especially against negative symptoms, without causing EPSPs (see Chapter 9). 

Olivier, B, van Wijngaarden, I and Soudijn, W (2000) 5-HT3-receptor antagonists and anxiety a preclinical and clinical view. Eur. Neuropsychopharmacol. 10 77-95. 

Droperidol or a 5-HT3 receptor antagonist should be administered at the end of surgery to patients at high risk for developing postoperative nausea and vomiting. 

The CTZ, located outside the blood-brain barrier (BBB), is exposed to cerebrospinal fluid and blood.2,3 Therefore it is easily stimulated by uremia, acidosis, and the circulation of toxins such as chemotherapeutic agents. The CTZ has many serotonin type 3 (5-HT3), neurokinin-1 (NKj), and dopamine (D2) receptors.2 Visceral vagal nerve fibers are rich in 5-HT3 receptors. They respond to gastrointestinal distention, mucosal irritation, and infection. 

Two 5-HT receptor sub-types, 5-HT3 and 5-HT4, are involved in gut motility, visceral sensitivity, and gut secretion. The 5-HT3 receptors slow colonic transit and increase fluid absorption, whereas 5-HT4 receptor stimulation results in accelerated colonic transit. 

Stimulation of 5-HT3 receptors triggers hypersensitivity and hyperactivity of the large intestine. Alosetron (Lotronex) is a selective 5-HT3 antagonist that blocks these receptors and is used to treat women with severe diarrhea-predominant IBS. Eligible patients should have frequent and severe abdominal pain, frequent bowel urgency or incontinence, and restricted daily activities. Alosetron has been shown to improve overall symptoms and quality of life. Alosetron can cause constipation in some patients. 

Evaluate 5-HT3 receptor antagonists (alosetron) for relief of abdominal pain and fecal incontinence. 

There are three main drug targets that are antagonized to prevent or treat acute and delayed CINV 5-HT3 receptors, dopamine type 2 receptors (D2), and NK-1 receptors. 5-HT3-receptor antagonists are the most effective agents for preventing... 

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