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

The authors review both the preclinical and the clinical evidence for a role of serotonin (5-HT) systems in the regulation of drug-taking behavior. Animal studies show that pharmacologic treatments that enhance 5-HT function, notably selective reuptake inhibitors, reduce the self-administration of a variety of substances of abuse, including ethanol and cocaine. These treatments also tend to suppress consummatory behavior in general. In contrast to the broad spectrum of suppression following 5-HT enhancement, selective antagonists at the 5-HT3 receptor subtype have been reported to reduce ethanol but not cocaine or food intake. Although essentially limited to alcohol abusers, clinical studies seem to support the preclinical findings that a number of 5-HT reuptake inhibitors decrease interest in and intake of alcohol in mild-moderate ethanol-dependent individuals. Furthermore, other serotonergic drugs may show utility in the treatment of alcohol abuse. Another way in which serotonergic medications can be used in treating substance abuse is by the treatment of comorbid psychoactive illness for which such drugs are already known to be effective, e.g., depression and anxiety disorders.
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PMID:Opportunities for treatment of psychoactive substance use disorders with serotonergic medications. 175 60

Benzodiazepines (BDZ), the most popular drug of choice for treating anxiety disorders, present side-effects such as sedation, muscular disorders, abuse liability and synergistic effect with alcohol and CNS depressant drugs. At present, pharmacological research is focusing to find anxiolytic drugs as efficacious as benzodiazepines but without side-effects. This review reports the status of the pharmaceutical research and development on novel drugs for the treatment of anxiety disorders. A close analysis of the items selected by the N5C "Pharmaprojects" search (anxiolytic class) yielded the following classification: A) Drugs interacting with the GABA-A receptor complex, which includes BDZ-like drugs, partial BDZ agonists (beta-carbolines) and drugs interacting with the GABA-A complex through an as yet unidentified mechanism (15 compounds), B) Drugs acting as CCK-B antagonists (5 compounds), C) Drugs interacting with serotonergic function (30 compounds) subdivided into: (i) agonists at the 5-HT1A receptor, (ii) antagonists at the 5-HT2 receptor, and (iii) antagonists at the 5-HT3 receptor; D) Drugs with other mechanisms (22 compounds). Based on these results, it is not possible to identify a common mechanism through which the selected drugs under development exert their anxiolytic effect. Therefore, it appears that different biological mechanisms are specifically involved in the different anxiety disorders.
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PMID:New anxiolytics in development. 791 35

In an attempt to develop new animal models of anxiety with face and predictive validity for the spectrum of human anxiety disorders, two new animal paradigms have been described, stress-induced hyperthermia (SIH) in mice and ultrasonic pup vocalizations (UV) in rats. In SIH mice develop enhanced body temperature in anticipation of an aversive event. This SIH can be antagonized by benzodiazepines, alcohol and 5-HT1A receptor agonists, but not by specific 5-HT reuptake inhibitors (SSRIs) or 5-HT3 receptor antagonists. When rat pups are separated from their mother and littermates they produce ultrasonic sounds, indicative of a separation distress. Benzodiazepines, 5-HT1A receptor agonists and SSRIs decrease this calling, whereas 5-HT3 receptor antagonists have no effect. Antidepressants in general do not decrease pup calling because in contrast to the SSRIs, noradrenergic uptake blockers enhance calling. These two animal models of anxiety can be added to the range of anxiety models and will be of help in predicting new putative anxiolytic drugs.
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PMID:New animal models of anxiety. 791 48

It seems that psychopharmacology may be well on its way toward the goal of developing new anxiolytic drug(s) that are fast acting and free from the unwanted effects associated with the traditional benzodiazepines. Several specific candidates exist, based upon rational targeting of neurotransmitter receptors shown to be linked to the neurobiology of anxiety. Thus, partial agonists at the benzodiazepine receptor, such as alpidem, abecarnil, and bretazenil, have highly promising preclinical profiles, and some useful preliminary results in clinical testing of anxiety disorder subjects. Neurosteroids are another interesting set of pharmacologic agents that target the benzodiazepine receptor, have a preclinical anxiolytic profile, and now need to be tested in clinical populations. Targeting of various serotonin (5HT) receptor subtypes is a very active area of current research for novel anxiolytic agents. 5HT3 antagonists may have an anxiolytic profile, but clinical results are still preliminary and need more validation. Of considerable interest is the idea of developing new drugs that act at 5HT1A, 5HT2A, or 5HT2C receptors. It has even been proposed that simultaneous targeting of both 5HT2A and 5HT1A receptors could result in robust anxiolytic agents that will have more immediate onset of action than currently available 5HT1A receptor acting drugs. Neuropeptide receptor agonists and antagonists with anxiolytic properties may represent one of the most striking new classes of potential anxiolytic drugs, but this is an emerging field that still requires considerably more systematic clinical testing. Nevertheless, preclinical studies as well as early clinical studies suggest that at least three neuropeptide receptors are provocative targets for novel anxiolytic agents: namely antagonists for CCK-B receptors, antagonists for CRF receptors, and agonists for neuropeptide Y receptors. Rational development of new pharmacologic agents based upon targeting receptors for those neurotransmitters that regulate the neurobiology of anxiety promises to bring forth a number of exciting therapeutic agents for the treatment of anxiety disorders in the future.
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PMID:Future directions in anxiolytic pharmacotherapy. 874 88

This study deals with the effects of the 5-HT3 receptor antagonist, BRL 46470A, on memory and anxiety, using the elevated T-maze. This method is useful for investigating the effects of anxiolytic drugs on memory, and the relationships between neural subsystems involved in emotionally related behaviors and in processes underlying learning. After the drug was either injected peripherally or microinjected into the amygdala, the animals were tested on the elevated T-maze (30 or 15 min later, respectively). Two kinds of aversively motivated behaviors, inhibitory avoidance and one-way escape, were recorded. These behaviors may reflect different types of fear/anxiety, namely, anticipatory anxiety and innate fear. Three days later, memory for these tasks was assessed by reexposing the subjects to the maze. The compound had an anxiolytic effect on the inhibitory avoidance response when given systemically, but an anxiogenic effect when injected into the amygdala. It had an anxiolytic action on the escape response when given either systemically or into the amygdala. The compound had no adverse effects on memory for either task. These results suggest that this new 5-HT3 antagonist may be useful in the treatment of certain types of anxiety disorders, especially those related to unconditioned fear, e.g. phobic or panic disorders, with the likelihood of having no side effects on memory processes. The contrasting results obtained with different measures of anxiety may also account for the inconsistencies found in the experimental literature dealing with compounds of this nature.
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PMID:Effects of anxiety and memory of systemic and intra-amygdala injection of 5-HT3 receptor antagonist BRL 46470A. 884 Mar 42

The discovery of multiple subtypes of the serotonin 5-HT receptor has generated enormous interest over the past few years. Possibly the most exciting, in terms of psychiatric clinical practice, appeared to be the 5-HT3 receptor. Early animal studies suggested that the 5-HT3 receptor antagonists, in addition to their well recognised antiemetic use, might be clinically useful in a number of areas. These included anxiety disorders, psychotic disorders, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, the treatment of pain and the treatment of irritable bowel syndrome. With the exception of antiemetic actions, this review examines these potential therapeutic areas carefully, paying particular attention not only to the animal literature, but to the clinical studies which have resulted from these initial findings. Unfortunately, studies in many of these therapeutic areas have not lived up to their initial promise. Indeed, no clinical studies have yet clearly demonstrated the usefulness of 5-HT3 receptor antagonists in the treatment of CNS disorders. Nonetheless, in view of the absence of published results from double-blind, placebo-controlled studies in many of these therapeutic areas, further research would be useful in confirming the effectiveness, or otherwise, of this group of compounds.
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PMID:The non-antiemetic uses of serotonin 5-HT3 receptor antagonists. Clinical pharmacology and therapeutic applications. 901 Jun 47

To date, more than two thousand experiments have investigated the behavioral effect of 5-HT-interacting drugs in animal models of anxiety disorders. Most of them have focused on the involvement of drugs interacting with 5-HT1A, 5-HT2A/2C and 5-HT3 receptors. Although numerous results are in line with the classic 5-HT hypothesis of anxiety, suggesting that decreased anxiety is related to decreased activity in central 5-HT neurons and vice versa, paradoxical drug effects have often been found. To explain this variability, several authors point to a determining role of the experimental paradigms used. In fact, an overview of the behavioral data arising from the vast literature indicates that conditioned procedures as well as more ethological-based tests are equal in revealing anxiolytic-like effects of drugs targetting 5-HT1A, 5-HT2A or 5-HT2C receptor subtypes. Furthermore, results obtained in ethologically-based animal models of anxiety with drugs stimulating 5-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they showed an increase in animals' emotional reactivity. Finally, anxiolytic-like effects of 5-HT3 receptor antagonists are in great part revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes, are involved in the genesis of anxiety.
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PMID:Variability in the effects of 5-HT-related compounds in experimental models of anxiety: evidence for multiple mechanisms of 5-HT in anxiety or never ending story? 911 42

Serotonin is implicated in the etiology of anxiety disorders and in the anxiolytic actions of benzodiazepines. Preclinical studies with 5-HT3 receptor antagonists, including ondansetron, show they have anxiolytic properties and that ondansetron suppresses withdrawal anxiety after abrupt discontinuation of chronic benzodiazepine treatment. We evaluated the efficacy of ondansetron as an adjunctive medication in the discontinuation of benzodiazepines in long-term users. One hundred eight patients who had used alprazolam or lorazepam regularly for > 3 months entered, and 97 completed a randomized double-blind discontinuation treatment program during which they received either ondansetron 2 mg twice daily or placebo and flexibly tapered their benzodiazepine over a 6-week period. There were no significant differences between the patients who had entered and completed treatment. Three weeks postmedication, 63% of the patients discontinued use of benzodiazepine. The percentage of reduction of benzodiazepine daily dosage at all time points in the treatment trial was similar for the ondansetron and placebo groups. Ondansetron had no significant effects on severity of withdrawal symptoms or levels of anxiety. High placebo response may have prevented detection of an ondansetron effect. At 1 year follow-up, 68% of patients reported that they stopped using benzodiazepine. Patient characteristics were more important than ondansetron in tapered benzodiazepine discontinuation.
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PMID:A controlled trial of ondansetron, a 5-HT3 antagonist, in benzodiazepine discontinuation. 955 97

Lotronex (alosetron hydrochloride) is a 5-HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP 2C9 and 3A4. Alprazolam is a short-acting benzodiazepine commonly prescribed for the treatment of anxiety disorders and a potential comedication in patients with IBS. Alprazolam is extensively metabolized by CYP3A4. This clinical study was conducted to assess the potential for a metabolic drug interaction between these two CYP3A4 substrates. This was an open-label, randomized, two-period, crossover study in 12 healthy female and male volunteers to determine the effect of concomitant administration of alosetron at the recommended dose of 1 mg p.o. bid on the pharmacokinetics of alprazolam following a single oral 1 mg dose. The results showed no effect of alosetron on the pharmacokinetics of alprazolam. Mean alprazolam AUC was 210 and 202 ng.h/mL in the absence and the presence of alosetron, respectively. Therefore, alprazolam may be safely coadministered with alosetron without the need for dosage adjustment.
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PMID:Effect of alosetron on the pharmacokinetics of alprazolam. 1130 2

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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