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The Journal of Physiology Jan 2009The attenuation of food intake as induced by an increase in serotonergic (5-hydroxytryptamine, 5-HT) efficacy has been a target of antiobesity pharmacotherapies.... (Review)
Review
The attenuation of food intake as induced by an increase in serotonergic (5-hydroxytryptamine, 5-HT) efficacy has been a target of antiobesity pharmacotherapies. However, the induction of tolerance and/or side-effects limited the clinical utility of the earliest serotonin-related medications. With the global prevalence of obesity rising, there has been renewed interest in the manipulation of the serotonergic system as a point of pharmacological intervention. The serotonin(2C) receptor (5-HT(2C)R), serotonin(1B) (rodent)/serotonin(1Dbeta) (human) receptor (5-HT(1B/1Dbeta)R) and serotonin(6) receptor (5-HT(6)R) represent the most promising serotonin receptor therapeutic targets. Canonical serotonin receptor compounds have given way to a myriad of novel receptor-selective ligands, many of which have observable anorectic effects. Here we review serotonergic compounds reducing ingestive behaviour and discuss their clinical potential for the treatment of obesity.
Topics: Animals; Appetite Regulation; Eating; Fenfluramine; Humans; Hypothalamus; Mice; Mice, Knockout; Models, Neurological; Obesity; Receptors, Serotonin; Serotonin; Serotonin Agents
PubMed: 19029184
DOI: 10.1113/jphysiol.2008.164152 -
British Journal of Pharmacology Jan 2006This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists....
This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5-HT in 1949. The presence of 5-HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5-HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5-HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5-HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5-HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5-HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor-specific drugs and use the information gained to better treat central nervous system disorders.
Topics: Animals; Antidepressive Agents; Brain; History, 20th Century; History, 21st Century; Humans; Receptors, Serotonin; Serotonin; Serotonin Agents; United Kingdom
PubMed: 16402098
DOI: 10.1038/sj.bjp.0706427 -
Biochimie Jun 2019Membrane receptors often form complexes with other membrane proteins that directly interact with different effectors of the signal transduction machinery.... (Review)
Review
Membrane receptors often form complexes with other membrane proteins that directly interact with different effectors of the signal transduction machinery. G-protein-coupled receptors (GPCRs) were for long time considered as single pharmacological entities. However, evidence for oligomerization appeared for various classes and subtypes of GPCRs. This review focuses on metabotropic serotonin (5-hydroxytryptamine, 5-HT) receptors, which belong to the rhodopsin-like class A of GPCRs, and will summarize the convergent evidence that homo- and hetero-dimers containing 5-HT receptors exist in transfected cells and in-vivo. We will show that complexes involving 5-HT receptors may acquire new signal transduction pathways and new physiological roles. In some cases, these complexes participate in disease-specific deregulations, that can be differentially affected by various drugs. Hence, selecting receptor complex-specific responses of these heterodimers may constitute an emerging strategy likely to improve beneficial therapeutic effects.
Topics: Animals; Humans; Ligands; Protein Multimerization; Receptors, Serotonin; Signal Transduction
PubMed: 30685449
DOI: 10.1016/j.biochi.2019.01.009 -
Pharmacology, Biochemistry, and Behavior Jun 2014In this review, first a historical perspective of serotonin's (5-HT) involvement in female sexual behavior is presented. Then an overview of studies implicating 5-HT is... (Review)
Review
In this review, first a historical perspective of serotonin's (5-HT) involvement in female sexual behavior is presented. Then an overview of studies implicating 5-HT is presented. The effect of drugs that increase or decrease CNS levels of 5-HT is reviewed. Evidence is presented that drugs which increase 5-HT have negative effects on female sexual behavior while a decrease in 5-HT is associated with facilitation of sexual behavior. Studies with compounds that act on 5-HT₁, 5-HT₂ or 5-HT₃ receptors are discussed. Most evidence indicates that 5-HT₁A receptor agonists inhibit sexual behavior while 5-HT₂ or 5-HT₃ receptors may exert a positive influence. There is substantial evidence to support a role for 5-HT in the modulation of female consummatory sexual behavior, but studies on the role of 5-HT in other elements of female sexual behavior (e.g. desire, motivation, sexual appetite) are few. Future studies should be directed at determining if these additional components of female sexual behavior are also modulated by 5-HT.
Topics: Animals; Female; Humans; Receptor Cross-Talk; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sexual Behavior; Sexual Behavior, Animal
PubMed: 24239784
DOI: 10.1016/j.pbb.2013.11.008 -
Current Biology : CB Jul 1997The type of RNA editing that converts adenosine to inosine in double-stranded RNA generates different isoforms of subunits of the ionotropic glutamate-gated ion channel... (Review)
Review
The type of RNA editing that converts adenosine to inosine in double-stranded RNA generates different isoforms of subunits of the ionotropic glutamate-gated ion channel receptors. Recently, it has been reported that the pre-mRNA of the serotonin 2C receptor can be edited by the same mechanism.
Topics: Adenosine Deaminase; Animals; Humans; RNA Editing; RNA Precursors; RNA-Binding Proteins; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin
PubMed: 9210370
DOI: 10.1016/s0960-9822(06)00212-0 -
Bioorganic & Medicinal Chemistry Aug 20165-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such...
5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.
Topics: Carbon-13 Magnetic Resonance Spectroscopy; Isoquinolines; Ligands; Proton Magnetic Resonance Spectroscopy; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin
PubMed: 27312422
DOI: 10.1016/j.bmc.2016.05.053 -
European Neuropsychopharmacology : the... Mar 2000The present paper reviews the evidence for anxiolytic activity of 5-HT(3) receptor antagonists in animal models of anxiety and in clinical trials in humans. Compared to... (Review)
Review
The present paper reviews the evidence for anxiolytic activity of 5-HT(3) receptor antagonists in animal models of anxiety and in clinical trials in humans. Compared to the established anxiolytics (benzodiazepine receptor agonists and, to a lesser extent, 5-HT(1A) receptor agonists) 5-HT(3) receptor antagonists display a different anxiolytic profile. They are anxiolytic in a limited number of animal anxiety models. If active, they often are very potent and display bell-shaped dose response curves, whereas the ratio between therapeutic activity and side effects appears remarkably large. 5-HT(3) receptor antagonists remain active after chronic dosing and no indications for tolerance, dependence or rebound effects were found, which seems to make these drugs an attractive alternative to the benzodiazepines. However, the large body of animal data indicating a complete lack of psychotropic activity of 5-HT(3) receptor antagonists weakens the prediction of anxiolytic activity in these drugs. Human data are also controversial; some investigators have reported positive effects in anxiety disorders (panic disorder, GAD), others did not. It can be concluded that 5-HT(3) receptor antagonists do not represent a breakthrough in the treatment of various anxiety disorders, as initially suggested.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Disease Models, Animal; Humans; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists
PubMed: 10706989
DOI: 10.1016/s0924-977x(99)00065-6 -
Neuroscience Sep 2011Learning and memory in the fruit fly, Drosophila melanogaster, is a complex behavior with many parallels to mammalian learning and memory. Although many...
Learning and memory in the fruit fly, Drosophila melanogaster, is a complex behavior with many parallels to mammalian learning and memory. Although many neurotransmitters including acetylcholine, dopamine, glutamate, and GABA have previously been demonstrated to be involved in aversive olfactory learning and memory, the role of serotonin has not been well defined. Here, we present the first evidence of the involvement of individual serotonin receptors in olfactory learning and memory in the fly. We initially followed a pharmacological approach, utilizing serotonin receptor agonists and antagonists to demonstrate that all serotonin receptor families present in the fly are necessary for short-term learning and memory. Isobolographic analysis utilizing combinations of drugs revealed functional interactions are occurring between 5-HT(1A)-like and 5-HT(2), and 5-HT(2) and 5-HT(7) receptor circuits in mediating short-term learning and memory. Examination of long-term memory suggests that 5-HT(1A)-like receptors are necessary for consolidation and important for recall, 5-HT(2) receptors are important for consolidation and recall, and 5-HT(7) receptors are involved in all three phases. Importantly, we have validated our pharmacological results with genetic experiments and showed that hypomorph strains for 5-HT(2)Dro and 5-HT(1B)Dro receptors, as well as knockdown of 5-HT(7)Dro mRNA, significantly impair performance in short-term memory. Our data highlight the importance of the serotonin system and individual serotonin receptors to influence olfactory learning and memory in the fly, and position the fly as a model system to study the role of serotonin in cognitive processes relevant to mammalian CNS function.
Topics: Animals; Brain; Conditioning, Classical; Drosophila melanogaster; Female; Learning; Male; Memory; Receptors, Serotonin; Smell
PubMed: 21749913
DOI: 10.1016/j.neuroscience.2011.06.058 -
Molecular Brain Jul 2014Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple... (Review)
Review
Serotonin receptors are G-protein-coupled receptors (GPCRs) involved in a variety of psychiatric disorders. G-proteins, heterotrimeric complexes that couple to multiple receptors, are activated when their receptor is bound by the appropriate ligand. Activation triggers a cascade of further signalling events that ultimately result in cell function changes. Each of the several known G-protein types can activate multiple pathways. Interestingly, since several G-proteins can couple to the same serotonin receptor type, receptor activation can result in induction of different pathways. To reach a better understanding of the role, interactions and expression of G-proteins a literature search was performed in order to list all the known heterotrimeric combinations and serotonin receptor complexes. Public databases were analysed to collect transcript and protein expression data relating to G-proteins in neural tissues. Only a very small number of heterotrimeric combinations and G-protein-receptor complexes out of the possible thousands suggested by expression data analysis have been examined experimentally. In addition this has mostly been obtained using insect, hamster, rat and, to a lesser extent, human cell lines. Besides highlighting which interactions have not been explored, our findings suggest additional possible interactions that should be examined based on our expression data analysis.
Topics: Animals; Brain; GTP-Binding Proteins; Humans; Protein Binding; Protein Isoforms; Protein Multimerization; Receptors, Serotonin
PubMed: 25011628
DOI: 10.1186/s13041-014-0049-y -
Pharmacogenomics May 2008The 5-HT(3) receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT(3AE), which are encoded by the... (Review)
Review
The 5-HT(3) receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT(3AE), which are encoded by the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E, respectively. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes seem to be involved in chemotherapy-induced nausea and vomiting (CINV), irritable bowel syndrome and psychiatric disorders. 5-HT(3) receptor antagonists are established in the therapy of CINV and irritable bowel syndrome. HTR3A and HTR3B polymorphisms may also contribute to the etiology of psychiatric disorders and serve as predictors in CINV and in the medical treatment of psychiatric patients.
Topics: Animals; Databases, Genetic; Genetic Variation; Humans; Receptors, Serotonin; Receptors, Serotonin, 5-HT3
PubMed: 18466097
DOI: 10.2217/14622416.9.5.501