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)

Recent experimental data, both in animals and the clinic, suggest that drugs selectively interacting with the 5-HT system may reduce alcohol intake. Although the precise mechanisms underlying these drug effects are unknown, it seems that there are at least two pharmacological strategies available, described in this review by Edward Sellers and colleagues. The first is enhancement of 5-HT neuronal activity using compounds that will release 5-HT, block 5-HT reuptake, or act as selective 5-HT receptor agonists. A second approach involves selective 5-HT3 receptor antagonists. If the initial research findings with these drugs are confirmed and extended, they may present useful therapies for the treatment of alcohol abuse, especially if used in conjunction with psychosocial therapy.
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PMID:5-HT and alcohol abuse. 156 16

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

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 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

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

The effects of the receptor antagonists MDL 72222 (MDL, 5-HT3) and naltrindole (delta-opioid) on ethanol reward and its discrimination were examined in ethanol-preferring C57BL/6 (C57) mice. MDL attenuated lever responding for 12% ethanol delivered on a fixed-ratio 8 reinforcement schedule at a dose that did not influence responding for water reward, thus confirming a previous report that ICS 205-930 reduced ethanol reward for Long-Evans rats. Our study in combination with the reduced ethanol consumption reported for C57 mice injected with odansetron indicates that 5-HT3 receptor systems are involved in mediating behavior directed toward obtaining ethanol as well as its consumption. By attenuating the rewarding effects of ethanol or of ethanol conditioned cues (e.g., the operant environment), 5-HT3 antagonists may be useful in the treatment of alcohol abuse. The 5-HT3 antagonist effects in this study are comparable with the effects of naltrexone on ethanol reward in C57 mice, although higher doses were required to reduce operant responding for ethanol reward. In contrast to the 5-HT3 antagonist and naltrexone effects, naltrindole, an antagonist with greater specificity for the delta-opioid receptor, was without effect on ethanol reward. This result and recent reports for rats and monkeys suggests that the general antagonists might be more efficacious in attenuating ethanol reward. Both MDL and naltrindole produced only slight reductions in the ethanol discriminative cue, suggesting that the rewarding and discriminative effects of ethanol are not likely mediated by identical neural mechanisms as previously suggested.
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PMID:Delta-opioid and 5-HT3 receptor antagonist effects on ethanol reward and discrimination in C57BL/6 mice. 1063 48

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

The 5-HT3 receptor is a ligand-gated cation channel located in the central and peripheral nervous system; it has also been detected on a variety of other cells. In the periphery, it is found on autonomic neurons and on neurons of the sensory and enteric nervous system. In the CNS, the 5-HT3 receptor has been localized in the area postrema, nucleus tractus solitarii, nucleus vaudatus, nucleus accumbens, amygdala, hippocampus, entorhinal, frontal, cingulate cortex, and in the dorsal horn ganglia. Further extraneuronal locations include among others lymphocytes, monocytes, and foetal tissue. 5-HT3 receptors modulate the release of neurotransmitters and neuropeptides like dopamine, cholecystokinin, acetylcholine, GABA, substance P, and serotonin itself. They have been demonstrated to be involved in sensory transmission, regulation of autonomic functions, integration of the vomiting reflex, pain processing and control of anxiety. While the physiologic functions of the 5-HT3 receptor are discrete and difficult to detect, it plays a key role in certain pathologic situations related to increased serotonin release. Clinical development of 5-HT3 receptor antagonists revealed a remarkable range of activities. 5-HT3 receptor antagonists do not modify any aspect of normal behaviour in animals or induce pronounced changes of physiological functions in healthy subjects. Clinical efficacy was shown for various forms of emesis like chemotherapy-induced, radiotherapy-induced, and postoperative emesis, diarrhoea-predominant irritable bowel syndrome, anxiety, chronic fatigue syndrome, alcohol abuse, and in pain syndromes such as fibromyalgia and migraine. Most recent data also suggest that 5-HT3 receptor antagonists are effective for the treatment of other rheumatic diseases such as rheumatoid arthritis, tendinopathies, periarthropathies, and myofascial pain. Other possible indications under discussion are chronic heart pain and bulimia. Unfortunately, experimental findings do not yet provide a homogenous conception of the significance of 5-HT3 receptors in all investigated fields; in nociception, for example, contradictory observations are still inadequately explained and complicated by bell-shaped dose-response curves. Further elucidation and better understanding of the serotonergic neuronal network remains a task for the next decade.
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PMID:Physiology and pathophysiology of the 5-HT3 receptor. 1551 4