Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serotonin system has long been thought to play a role at several steps in the cycle of alcohol abuse. Initial motivation may be triggered by anxiety, which may exhibit a serotonergic component (5-HT1A receptor). Alcohol can potentiate the opening of 5-HT3 receptor ion channels, and agents which elevate serotonergic tone, including serotonergic agonists, uptake inhibitors and releasers, have shown promise in assisting with recovery from alcoholism. In this review, recent advances in serotonin receptor research are presented, with a special emphasis on the impact and interpretation of molecular biological data. Genetic and pharmacological concepts of receptor subtypes are reviewed and related to a new classification system for the 14 currently recognized subtypes of serotonin receptors. The current and likely future impact on drug design of the molecular approach to serotonin receptors is discussed. Finally, the question of why there are so many serotonin receptor subtypes is examined, along with possible roles of multiple G protein and second messenger pathways, and their effect on conserved domains of these receptor proteins.
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PMID:Molecular pharmacology of serotonin receptors. 751 66

The present study was performed to examine the involvement of serotonin-3 (5-HT3) receptors in the rat nucleus accumbens (ACC) in alcohol dependence. In alcohol-treated rats, perfusion of 40 mM K+ and 100 mM ethanol (EtOH) through the microdialysis probe increased the extracellular levels of ACC dopamine (DA), compared with controls. Perfusion of the serotonin (5-HT) uptake inhibitor sertlarine enhanced the extracellular levels of ACC 5-HT in both groups. Increased 5-HT availability in the synaptic clefts on the ACC further activated ACC DA release in the alcohol-treated rats, in comparison with controls. In the final experiments, perfusion of the 5.0 microM 5-HT3 receptor agonist 2-methyl-5-HT (2-Me-5-HT) through the microdialysis probe enhanced the extracellular levels of ACC DA. Magnitude of 2-Me-5-HT-induced DA release was significantly higher in alcohol-treated rats than in controls. On the other hand, 40 mM K(+)- and 100 mM EtOH-induced extracellular 5-HT release in alcohol-treated rats were markedly inhibited. These results show that (1) chronic alcohol intake increases the sensitivity of 5-HT3 receptors, (2) 5-HT3 receptors regulate DA release in the ACC, (3) the dopaminergic neuronal systems associated with 5-HT3 ionophore in the ACC were upregulated after chronic alcohol exposure, and (4) chronic alcohol intake desensitizes the serotonergic neuronal systems in rat ACC. These findings suggest that neurochemical functions of 5-HT3 receptors in regulating DA release in the ACC after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance and that the development of alcohol dependence may be mediated by ACC 5-HT3 receptors.
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PMID:Possibility of 5-HT3 receptor involvement in alcohol dependence: a microdialysis study of nucleus accumbens dopamine and serotonin release in rats with chronic alcohol consumption. 898 29

The 5-HT3 receptor is a ligand-gated ion channel activated by the neurotransmitter serotonin. Receptors of this subtype have been localized to several regions of the brain, and appear to be involved in many neuronal functions including responses to alcohol and other drugs of abuse. There is an extensive and growing literature indicating that 5-HT3 receptors are involved in several facets of alcohol seeking behavior, alcohol intoxication and addiction. In addition, there is strong evidence that alcohols, including ethanol, alter the function of the 5-HT3 receptor, possibly through actions on the receptor protein itself. In this article, our current understanding of the role of the 5-HT3 receptor in alcohol abuse and alcoholism will be reviewed. In addition, an overview of current understanding of the mechanism of alcohol actions of the receptor is provided.
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PMID:5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic. 1040 96

Ethanol sensitivity may play a role in the risk of developing alcoholism. The role of 5-HT3 receptors in sensitivity to ethanol was assessed in mice over-expressing the 5-HT3 receptor in the forebrain. Sleep time and ED50 for loss of righting reflex (LRR) were used to assess the effect of a high dose of ethanol in transgenic versus non-transgenic mice. The ED50 for ethanol-induced increase in open field activity was used to measure differences in sensitivity to low dose ethanol. The ED50 for ethanol-induced increase in activity was 41% lower in the 5-HT3 receptor over-expressing transgenic mice compared to non-transgenic mice. However, 5-HT3 receptor over-expressing mice did not differ from control mice in ethanol metabolism, ED50 for LRR, and ethanol sleep time. Over-expression of 5-HT3 receptors in mouse forebrain results in an enhanced sensitivity to the stimulating effects of a low dose of ethanol without altering ethanol sedating effects or ethanol metabolism. These data suggest that 5-HT3 receptors modulate low dose ethanol sensitivity and may explain why, in previous studies, these mice consume less ethanol.
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PMID:5-HT3 receptor over-expression enhances ethanol sensitivity in mice. 1043 15

The aim of the present study was to examine the influence of ifenprodil (a non-competitive NMDA receptor antagonist which also blocks 5-HT3 receptors and alpha1-adrenoceptors) on the effects of ethanol in the mouse in vivo and to elucidate the role of various receptors in these actions. The ethanol (4 g/kg i.p.)-induced sleeping time was shortened by ifenprodil 1 mg/kg but was not affected by ifenprodil 0.3 mg/kg, the 5-HT3 receptor antagonist ondansetron 0.03 mg/kg and the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) 0.01 mg/kg. Ifenprodil 10 mg/kg mimicked the alpha1-adrenoceptor antagonist prazosin 1 mg/kg in that it prolonged the hypnotic response to ethanol (no additive effect when both drugs were given in combination); this is compatible with an involvement of alpha1-adrenoceptors in this effect of ifenprodil. Chronic exposure to ethanol (7%) induced physical dependence. The severity of ethanol withdrawal was suppressed by ifenprodil 1 and 10 mg/kg. In conclusion, ifenprodil influences ethanol-related changes in mouse behaviour and may prove to be useful in the treatment of alcoholism.
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PMID:Ifenprodil influences changes in mouse behaviour related to acute and chronic ethanol administration. 1044 20

It has long been postulated that an interaction between ethanol and stress may play an important role in the etiology of alcoholism. In the present review, we focused on an interaction between ethanol and stress in the mechanism of psychological dependence on ethanol. Ethanol with conditioned fear stress (CFS), but not without the stress, induced a significant place preference. These results suggest that psychological stress may play an important role in the rewarding effect of ethanol. It has been hypothesized that activation of the mesolimbic dopamine system mediated by the endogenous opioid system may be particularly important in the rewarding mechanism of ethanol. It appeared that mu- and delta-opioid receptors might play critical roles in the development of the rewarding effect of ethanol under the stress. Under psychological stress, the rewarding effect of ethanol through the activation of mu- and/or delta-opioid receptors was found to results the activation of dopamine D1 and/or D2 receptors. Additionally, a subtype of serotonin (5-HT) receptors, 5-HT3 receptor, was shown to be involved in the rewarding mechanism of ethanol through the activation of mu- and delta-opioid receptors. In conclusion, psychological stress may be an important factor in the development of the rewarding effect of ethanol and may potentiate the rewarding mechanism. 5-HT3 receptor, is likely to be involved in the rewarding mechanism of ethanol under stress. Dopamine D1 and D2 receptors may also be implicated in the rewarding mechanism of ethanol under stress.
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PMID:[Psychological stress and rewarding effect of alcohol]. 1213 20

This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The organizers and chairs were William J. McBride and David M. Lovinger. The presentations were (1) Mechanisms of alcohol potentiation of 5-HT3 receptor function, by David M. Lovinger and Tina Machu; (2) Chronic alcohol drinking alters 5-HT3 receptors regulating the mesolimbic dopamine system, by Richard J. Thielen; (3) 5-HT3 receptors in the VTA regulate alcohol drinking and the reinforcing effects of alcohol, by Zachary A. Rodd and James M. Murphy; and (4) Ondansetron as a treatment for "biological" alcoholism, by John D. Roache and Bankole A. Johnson.
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PMID:Serotonin-3 receptors in the actions of alcohol, alcohol reinforcement, and alcoholism. 1511 33

Opioid receptor antagonist naltrexone has shown some efficacy in decreasing ethanol consumption in humans. However, naltrexone treatment is not always efficacious and produces several aversive effects such as nausea, anxiety and weight loss. Serotonin-3 (5-HT3) receptor antagonists also modulate some of the behavioral effects of alcohol and may decrease alcohol consumption. We examined the effects of the combination of 5-HT3 receptor antagonist ICS 205-930 ((3-tropanyl-indole-1-carboxylate, tropisetron) and naltrexone on ethanol and food intake in Sprague-Dawley rats. Both naltrexone (0.56-10 mg/kg) and ICS 205-930 (5.6 mg/kg), when administered intraperitoneally 30 min before the scheduled 3-h access to ethanol, significantly suppressed ethanol intake. Naltrexone (1 mg/kg) when given in combination with ICS 205-930 (5.6 mg/kg) was significantly more efficacious in suppressing ethanol intake in comparison with naltrexone (1 mg/kg) administered alone. The drug combination did not affect the food intake. These data suggest that 5-HT3 receptor antagonist ICS 205-930 may be used as an effective adjunct for pharmacotherapy of alcoholism.
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PMID:5-HT3 antagonist ICS 205-930 enhances naltrexone's effects on ethanol intake. 1514 Jun 31

The ionotropic serotonin subtype-3 (5-HT3) receptor has emerged as a potential therapeutic target in the treatment of alcohol abuse and alcoholism because selective pharmacological antagonists reduce alcohol consumption in preclinical and clinical models. 5-HT binds to the extracellular N-terminus of the 5-HT(3A) receptor subunit but receptor activation is also enhanced by distinct allosteric sites, which indicates the presence of other receptor subunits. It is not known if specific molecular subunits of the 5-HT3 receptor modulate alcohol drinking. To address this issue, we characterized acute locomotor response to alcohol and alcohol consumption in a two-bottle home-cage procedure by congenic C57BL/6J mice with a targeted deletion of the 5-HT(3A) receptor subunit gene. 5-HT(3A)-null mice did not differ from wild-type littermate controls on measures of spontaneous locomotor activity, habituation to a novel environment, or locomotor response to ethanol (0, 0.5, 1, or 2 g/kg). Moreover, null mice did not differ from controls on measures of ethanol (2-10%) intake and preference during or after a two-bottle home-cage sucrose fading procedure. Systemic administration of the 5-HT3 antagonist LY-278,584 (0-10 mg/kg) decreased intake of both sweetened (2% sucrose+10% ethanol) and unsweetened (10% ethanol) ethanol in wild-type mice only. These findings indicate that reduction of alcohol drinking produced by 5-HT3 antagonism is dependent on the presence of 5-HT(3A)-containing receptors.
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PMID:5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking. 1516 58

Several 5-HT3 receptor antagonists are available (tropisetron, ondansetron, granisetron, dolasetron, and palonsetron), and further compounds are in clinical development. These substances show only minor differences in the activity profile regarding their affinity for particular receptors. 5-HT3 receptor antagonists are primarily used and found effective in the prevention and treatment of chemotherapy-induced nausea and emesis, and in postoperative nausea and vomiting (PONV). Antagonism of the 5-HT3 receptors in the peripheral and central nervous system is a probable mechanism of action. The substances are suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting. 5-HT3 receptor antagonists are an important constituent in the prevention and treatment of emesis and nausea caused by radiation therapy, especially in patients receiving whole body or upper abdominal treatment. Alosetron was found clinically effective in diarrhoea-predominant irritable bowel syndrome, whereas tropisetron in fibromyalgia and related pain disorders. Further indications for such treatment include anxiety disorders, alcohol dependence, drug withdrawal, and psychosis related to treatment of Parkinson's disease. 5-HT3 receptor antagonists are well tolerated with the most frequently reported adverse effects being headache, constipation, dizziness, tiredness, and gastrointestinal disturbances such as abdominal pain or constipation. Intravenous administration of serotonin induces the Bezold-Jarisch reflex and causes small reversible changes in electrocardiogram (ECG) parameters.
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PMID:Spectrum of use and tolerability of 5-HT3 receptor antagonists. 1551 6


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