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This chapter is a personal account of how the 5-HT2C receptor was discovered and characterized more than 25 years ago. 5-HT2C receptors, initially called 5-HT1C, were found while studying the distribution in the brain of binding sites for the compound mesulergine, a ligand with serotonergic and dopaminergic properties. The strong labeling to choroid plexus revealed a site with pharmacological properties...
The 5-HT2C receptor has, so far, been found exclusively in the central nervous system of mammalian species. 5-HT2C receptor binding sites are visualized by ligand binding autoradiography with different ligands, particularly mesulergine, and the distribution of the mRNA coding for this receptor has been identified by in situ hybridization. Immunohistochemical studies for the receptor protein with antibodies...
Over the past 15 years, there have been various attempts to rationally develop selective ligands for serotonin 5-HT2C receptor subtypes. To this end, the studies performed by researchers at GlaxoSmithKline have led to the identification of several potent and selective 5-HT2C receptor antagonists characterized by indole- or indoline-containing structure. The large body of data on antagonists has allowed...
Advances in cellular and molecular biology now allow investigators to generate small DNA constructs that can be substituted for specific genomic loci in mouse embryonic stem cells. The transgenic mice that are derived from embryos implanted with these engineered stem cells are powerful models for understanding protein function at molecular, cellular, tissue, and in vivo behavior levels of organization...
The neurotransmitter serotonin (or 5-hydroxytryptamine (5-HT)) binds to at least 14 structurally and pharmacologically distinct receptor subtypes. All 5-HT receptors with the exception of 5-HT3 receptor, which is a ligand-gated ion channel, belong to the seven- transmembrane domain G-protein-coupled receptor (GPCR) superfamily. Among all of 5-HT receptor subtypes, 5-HT2C receptor raises particular...
Achieving 5-HT2C selectivity is still a challenge for medicinal chemists. Luckily, they do not have to synthesize more or less blindly huge numbers of compounds hoping to obtain pharmacologically meaningful results since computational tools have been efficiently used to cope with this problem. 5-HT2C belongs to one of the largest drug target class, the G-protein-coupled receptors (GPCR). This makes...
G-protein-coupled receptor (GPCR) dimerization is a rapidly developing area of research. In recent years dimer/oligomer formation has been reported for dozens of different GPCR. Homo- and heterodimerization between different families of GPCR have been reported to regulate ligand binding, second messenger activation, and receptor trafficking. Twelve different serotonin receptor subtypes belonging to...
Serotonin receptor 2C (HTR2C) encodes a seven-transmembrane-spanning, G-protein-coupled receptor that activates phospholipase C. Mice deficient for this gene showed a range of behavioral alterations related to mental disorders. Linkage, association, and postmortem studies also suggested the involvement of this gene in the pathophysiology of mental disorders such as major depression and bipolar disorder...
The generation of new neurons and glia is a complex process that occurs in two discrete regions of adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the hippocampal formation. The development of these new cells is regulated by a number of intrinsic and extrinsic molecular mechanisms and modulated by physiological and pathological conditions. Regulatory factors...
Neurotransmitters usually interact with their receptors in a phasic and/or tonic manner. Additionally, numerous G-protein-coupled receptors display a constitutive activity that spontaneously activates intracellular pathways independently from the presence of the endogenous neurotransmitter. Although such multiple modalities of action have been clearly described in vitro, the transposition of the concept...
Several studies have focused on the role of serotonergic 5-HT2C receptors in the regulation of forebrain dopamine (DA) function and have highlighted their potential as a target for improved treatments of neuropsychiatric disorders related to central dopaminergic neuron dysfunction. This chapter was undertaken to summarize the authors’ and others’ works that have extensively explored the role of 5-HT...
There is considerable evidence supporting the involvement of serotonin-2C (5-HT2C) receptors in the pathophysiology of depression. First, 5-HT2C receptors play an important role in the regulation of monoamine transmission. Second, abnormalities in expression and functioning of 5-HT2C receptors have been observed in depressed patients and in animal models of depression. Third, a large body of evidence...
As a serious public health problem worldwide, suicide and related behaviors have merited a large body of research investigating their underlying biology. A number of studies suggest that a genetic component that is partly independent from the familial transmission of major psychiatric disorders may be involved in these behaviors. The serotoninergic system has been the neurotransmitter system most...
Clinical and preclinical evidence that suggests the serotonin-2C (5-HT2C) receptor plays a significant role in key elements of the pathophysiology of schizophrenia, including psychosis, negative symptoms, and the mechanism of action and side effects of antipsychotic drugs is reviewed here. The clinical evidence consists of phenotype-genotype studies linking one or more of three common polymorphisms...
Serotonin has long been known to exert inhibitory and excitatory influences over the activity of dopaminergic neurons. Electrophysiological and neurochemical evidence indicates that the inhibitory effect of 5-HT is mediated predominantly via the 5-HT2C receptor subtype. Given the major role that dopamine plays in reward-related behavior it is not surprising that ligands for 5-HT2C receptors modify...
Compelling evidence has shown that the 5-HT2C receptor might be a key target for treating drug addiction. While activation of the midbrain ventral tegmental area (VTA) dopamine neurons results in the rewarding effects common to all drugs of abuse, 5-HT2C agonists instead produce inhibition of these neurons. We recently discovered that the tumor suppressor PTEN (phosphatase and tensin homolog deleted...
It is well established that the central 5-hydroxytryptamine (5-HT) system plays critical roles in the regulation of energy homeostasis and in the processes of meal satiation and satiety. In this chapter the effects of serotonergic drugs on rodent and human appetite expression will be examined along with the effects of some of these drugs on body weight. Particular focus has been given to the 5-HT2C...
Serotonin-2C (5-HT2C) receptors are present in basal ganglia, a group of subcortical structures involved in motor behavior. These receptors are mediating the effect of 5-HT released in all these brain areas via terminal neurons coming mainly from the dorsal raphe nucleus. A growing interest has been brought to the function of 5-HT2C receptors in basal ganglia because they would be involved in the...
Tardive dyskinesia (TD), a movement disorder usually marked by persistent orofacial dyskinesia, was the frequent unintended outcome of long-term treatment of humans with conventional antipsychotic drugs. The condition was reproducible in other primates; also in rats, which display vacuous chewing movements (VCMs). Dopamine systems have long been regarded as having a prominent role in the development...
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