Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes. At present 15 receptor subtypes of three groups has been recognized. The 5-HT1 subfamily of receptors contains subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F; activation of all of them results in the inhibition of adenylylcyclase. The subfamily of 5-HT2 contains subtypes 5-HT2A, 5-HT2B, and 5-HT2C; their activation leads to the stimulation of PLC. Finally, subfamily of miscellaneous 5-HT receptors contains subtypes 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7; some of them has been cloned, however, our knowledge on their function is still minimal. 5-HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease. 5-HT plays an important role in depression; to cure this disease, drugs which increase levels of this neurotransmitter are used. A new drug group called Selective Serotonin Reuptake Inhibitors (SSRI) has been recently discovered. These drugs block the reuptake of 5-HT into nerve endings. There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential.
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PMID:[5-hydroxytryptamine (serotonin) receptors--nomenclature and classification of types and subtypes]. 758 16

Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtypes are linked to the multifunctional phosphoinositide (PI) signalling system. 5-HT3 receptors are considered ion-gated receptors and are also linked to the PI signalling system by an unknown mechanism. The 5-HT2A receptor subtype is the most widely studied of the 5-HT receptors in psychiatric disorders (for example, suicide, depression and schizophrenia) as well as in relation to the mechanism of action of antidepressant drugs. The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear. These 5-HT receptors also play an important role in alcoholism. It has been shown that 5-HT2A, 5-HT2C and 5-HT3 antagonists cause attenuation of alcohol intake in animals and humans. However, the exact mechanisms are unknown. The recent cloning of the cDNAs for 5-HT2A, 5-HT2C and 5-HT3 receptors provides the opportunity to explore the molecular mechanisms responsible for the alterations in these receptors during illness as well as pharmacotherapy. This review article will focus on the current research into the pharmacological properties, molecular biology, and clinical correlates of 5-HT2A, 5-HT2C and 5-HT3 receptors.
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PMID:Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. 778 83

Both glucocorticoid excess and decreased serotonergic (5-HT) transmission may cause depression. The recently cloned 5-HT6 and 5-HT7 receptors have high affinity for antidepressants. Here, we show that pharmacological adrenalectomy increases 5-HT6 and 5-HT7 receptor mRNA expression in specific hippocampal subfields, effects partly reversed by corticosterone replacement. Increased 5-HT6 and 5-HT7 receptor expression may provide a basis, in part, for the therapeutic actions of adrenal steroid synthesis inhibitors in resistant depression.
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PMID:Impact of adrenalectomy on 5-HT6 and 5-HT7 receptor gene expression in the rat hippocampus. 910 90

Interactions between neurotransmitter receptors involved in the pathophysiology of depression, anxiety and ethanol consumption and two extracts (hydromethanolic and lipophilic extracts obtained with hypercritical CO2) from Hypericum Perforatum L or St. John's wort (SJW) and three constituents (hyperforin, hypericin and biapigenin) were evaluated by in vitro binding assays. The two extracts, tested at 10 microg/ml, did not inhibit ligand binding at the following receptors: serotonin 5-HT6 and 5-HT7, benzodiazepine, sigma and neuropeptide Y (NPY) Y1 and Y2 receptors. The hydromethanolic extract, but not the lipophilic extract, interacted with GABA(A) receptors (IC50 5.5 microg/ml), while both interacted with the dopamine (DA) transporters, albeit with high IC50 values (24.5 and 12.9 microg/ml, respectively). Biapigenin (1 microg/ml, 2 microM) inhibited ligand binding at benzodiazepine receptors only (IC50: 2 microM). Hyperforin (1 microg/ml, 2 microM) only inhibited [3H]WIN-35,428 binding to DA transporters, although the IC50 (5 microM) was higher than the IC50 found for inhibition of the synaptosomal DA reuptake (0.8 microM). This finding extended the same observation previously described for the 5-HTergic system to the DAergic system, confirming that the inhibition of monoamine reuptake is due to a different mechanism than that of synthetic antidepressants. Hypericin showed micromolar affinities for both NPY-Y1 and Y2 receptors and for sigma receptors (IC50 3-4 microM). These hypericin activities might be of interest because NPY and sigma receptors have been associated with anxiety disorders, depressive illnesses and ethanol consumption. However, they were present at relatively high hypericin concentrations, and were also light-dependent (i.e. the IC50 values increased when binding assays were carried out in the dark). Thus, our in vitro binding results may suggest that either the pharmacological effects of SJW are due to other molecules than hypericin or hyperforin (other constituents or active metabolites), or that the mechanism of action is different from those that have been considered up to now.
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PMID:In vitro binding studies with two hypericum perforatum extracts--hyperforin, hypericin and biapigenin--on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transporters. 1151 75

5-HT research is now more than 50 years old, and it has generated a wealth of therapeutic agents, some of which have had a major impact on disease management. The 5-HT reuptake inhibitors (SSRIs) are among the most widely prescribed drugs for treating depression and a variety of other disorders including anxiety, social phobia and premenstrual dysphoria (PMD). The other major success stories of 5-HT research are the discovery of 5-HT1B/D receptor agonists for treating migraine and 5-HT3 receptor antagonists for chemotherapy and radiation-induced emesis. The role of 5-HT in the mechanism of action of antipsychotic agents remains a topic of intense research, which promises better treatments for schizophrenia in the future. Compounds interacting with 5-HT1F, 5-HT2C, 5-HT6 and 5-HT7 receptors are currently under investigation and may prove to have important therapeutic applications in the future.
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PMID:The medical benefit of 5-HT research. 1188 47

Previous genetic-response studies, usually without considering environmental factors, encountered great difficulties in replication of results. Although atypical antipsychotics are becoming the mainstay for schizophrenia treatment which makes an antipsychotic "atypical" remains unclear. Risperidone (a widely used atypical antipsychotic agent) and several other atypicals have high affinities for 5-HT6 and 5-HT7 receptors. This study investigated the effects of the T-->C 267 polymorphism in the 5HT6 receptor gene and two rare Pro279Leu and Thr92Lys substitutions in the 5HT7 receptor gene on risperidone efficacy after rigorous control for nongenetic confounders. We found an association between the T-->C 267 polymorphism of the 5HT6 receptor gene and response to risperidone in 123 acutely ill schizophrenia inpatients after adjustment for confounders. Compared to patients with the T/C 267 genotype, those with T/T 267 showed less severe positive symptoms (p=0.006) and general psychopathology (including anxiety, depression, and cognitive dysfunctions) (p=0.005). The T-->C 267 polymorphism had no influences on negative symptoms. The two rare polymorphisms in the 5HT7 receptor gene were not observed in our sample. In conclusion, the 5HT6 receptor gene variant can affect risperidone response to positive symptoms and general psychopathology (but not negative symptoms) after control for nongenetic factors.
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PMID:Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders. 1474 25

The purpose of the present study was to determine if a 5-HT6 receptor polymorphism is associated with antidepressant treatment response in major depressive disorder (MDD). Ninety-one patients with MDD, compared with 127 normal control subjects, were evaluated after an 8-week treatment period. An association analysis revealed no differences in genotype and allele distribution between patients with MDD and normal control subjects. However, there were significant differences in the treatment response in some Hamilton Depression Rating Scale (HAM-D) scores (sleep, activity, somatic anxiety, and total) between genotypes. Moreover, the heterozygote group (CT genotype) had significantly better treatment response than the homozygote group (CC + TT genotypes), especially in the somatic-anxiety subcategory and the total score of HAM-D. These findings imply that a 5-HT6 receptor polymorphism (C267T) is associated with treatment response in MDD.
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PMID:Association between the 5-HT6 receptor C267T polymorphism and response to antidepressant treatment in major depressive disorder. 1582 58

Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, alpha-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT2C, 5-HT6) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.
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PMID:Innovative approaches for the development of antidepressant drugs: current and future strategies. 1648 68

The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.
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PMID:Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease. 1843 76

Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus of concerted research efforts to identify new treatments for AD. 5-HT exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. With the subsequent development of selective 5-HT6 receptor antagonists, preclinical studies in rodents and primates have elucidated the function of this receptor subtype in more detail. It is increasingly clear that blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms and also results in anxiolytic and antidepressant-like activity. These actions are largely underpinned by enhancements of cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission, together with learning-associated neuronal remodeling. A preliminary report that the cognitive enhancing properties of a 5-HT6 receptor antagonist (namely, SB-742457) extends into AD sufferers further highlights the therapeutic promise of this mechanistic approach.
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PMID:5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. 1862 57


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