5-HT2A receptor

The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the is_associated_with::serotonin receptor family and is a G protein-coupled receptor (GPCR). This is the main excitatory receptor subtype among the is_associated_with::GPCRs for is_associated_with::serotonin (5-HT), although 5-HT2A may also have an inhibitory effect on certain areas such as the is_associated_with::visual cortex and the is_associated_with::orbitofrontal cortex. This receptor was first given importance as a target of serotonergic psychedelic drugs such as is_associated_with::LSD. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many is_associated_with::antipsychotic drugs, especially the atypical ones.

5-HT2A may be a necessary receptor for the spread of the human is_associated_with::polyoma virus called is_associated_with::JC virus.

Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of SSRIs and classical antipsychotics. Deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These findings suggest that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression.

History
Serotonin receptors were split into two classes by Gaddum and Picarelli when it was discovered that some of the serotonin-induced changes in the gut could be blocked by is_associated_with::morphine, whilst the remainder of the response was inhibited by dibenzyline leading to the naming of M and D receptors respectively. 5-HT2A is thought to correspond to what was originally described as D subtype of is_associated_with::5-HT receptors by Gaddum and Picarelli. In the pre-molecular-cloning era when is_associated_with::radioligand binding and displacement was the only major tool, spiperone and LSD were shown to label two different serotonin receptors, and neither of them displaced morphine, leading to naming of the 5-HT1, 5-HT2 and 5-HT3 receptors, corresponding to high affinity sites from is_associated_with::LSD, is_associated_with::spiperone and morphine respectively. Later it was shown that the 5-HT2 was very close to 5-HT1C and thus were clubbed together, renaming the 5-HT2 into 5-HT2A. Thus the 5-HT2 receptor family is composed of three separate molecular entities: the 5-HT2A (formerly known as 5-HT2 or D), the 5-HT2B (formerly known as 5-HT2F) and the 5-HT2C (formerly known as 5-HT1C) receptors.

Distribution
5-HT2A is expressed widely throughout the is_associated_with::central nervous system (CNS). It is expressed near most of the serotoninergic terminal rich areas, including is_associated_with::neocortex (mainly is_associated_with::prefrontal, parietal, and is_associated_with::somatosensory cortex) and the is_associated_with::olfactory tubercle. Especially high concentrations of this receptor on the is_associated_with::apical dendrites of is_associated_with::pyramidal cells in is_associated_with::layer V of the cortex may modulate cognitive processes, working memory,and attention  by enhancing is_associated_with::glutamate release followed by a complex range of interactions with the 5-HT1A, GABAA, adenosine A1, AMPA, mGluR2/3, mGlu5, and OX2 receptors. In the rat cerebellum, the protein has also been found in the is_associated_with::Golgi cells of the granular layer, and in the is_associated_with::Purkinje cells.

In the periphery, it is highly expressed in is_associated_with::platelets and many cell types of the is_associated_with::cardiovascular system, in is_associated_with::fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT2A mRNA expression has been observed in human is_associated_with::monocytes.

Signaling cascade
The 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways. Gαq stimulates is_associated_with::phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and is_associated_with::inositol triphosphate (IP3), which in turn stimulate is_associated_with::protein kinase C (PKC) activity and Ca2+ release.

There are many additional signal cascade components that include the formation of is_associated_with::arachidonic acid through is_associated_with::PLA2 activity, activation of is_associated_with::phospholipase D, Rho/is_associated_with::Rho kinase, and ERK pathway activation initiated by agonist stimulation of the receptor.

Effects
Physiological processes mediated by the receptor include:
 * CNS: neuronal excitation, behavioural effects, learning, anxiety
 * smooth muscle: contraction (in is_associated_with::gastrointestinal tract & is_associated_with::bronchi)
 * is_associated_with::vasoconstriction / is_associated_with::vasodilation
 * platelets: aggregation
 * Activation of the 5-HT2A receptor with DOI produces potent is_associated_with::anti-inflammatory effects in several tissues including cardiovascular and gut. Other 5-HT2A agonists like LSD also have potent anti-inflammatory effects against is_associated_with::TNF-alpha-induced is_associated_with::inflammation.
 * Activation of the 5-HT2A receptor in hypothalamus causes increases in hormonal levels of is_associated_with::oxytocin, is_associated_with::prolactin, is_associated_with::ACTH, is_associated_with::corticosterone, and is_associated_with::renin.
 * Role in memory

Agonists
Activation of the 5-HT2A receptor is necessary for the effects of the "classic" psychedelics like is_associated_with::LSD, is_associated_with::psilocin and is_associated_with::mescaline, which act as full or partial is_associated_with::agonists at this receptor, and represent the three main classes of 5-HT2A agonists, the is_associated_with::ergolines, is_associated_with::tryptamines and is_associated_with::phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their is_associated_with::structure-activity relationships have been extensively researched. Agonists acting at 5-HT2A receptors located on the is_associated_with::apical dendrites of is_associated_with::pyramidal cells within regions of the is_associated_with::prefrontal cortex are believed to mediate hallucinogenic activity. Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2A–mGlu2 and not by is_associated_with::monomeric 5-HT2A receptors. Agonists enhance dopamine in PFC, enhances memory and plays a role in attention and learning.

Full agonists

 * is_associated_with::25I-NBOH and its 2-methoxy-analog is_associated_with::25I-NBOMe
 * (R)-DOI
 * is_associated_with::TCB-2
 * is_associated_with::Bromo-DragonFLY
 * is_associated_with::Mexamine is a full agonist to several serotonin receptors.
 * is_associated_with::O-4310, 5-HT2A selective, claimed to have 100x selectivity over 5-HT2C and be inactive at 5-HT2B
 * is_associated_with::PHA-57378, dual 5-HT2A / 5-HT2C agonist, anxiolytic effects in animal studies.

Partial agonists

 * is_associated_with::25C-NBOMe
 * is_associated_with::Methysergide, a congener of is_associated_with::methylergonovine, used in treatment of is_associated_with::migraine blocks 5-HT2A and 5-HT2C receptors, but sometimes acts as partial agonist, in some preparations.
 * is_associated_with::OSU-6162 acts as a partial agonist at both 5-HT2A and dopamine D2 receptors
 * is_associated_with::25CN-NBOH, 100x selectivity for 5-HT2A over 5-HT2C, 46x selectivity over 5-HT2B.
 * is_associated_with::Juncosamine, is a structurally constrained derivative of is_associated_with::25B-NBOMe, which acts as a potent partial agonist with 124x selectivity for 5-HT2A over 5-HT2C, making it the most selective agonist ligand identified to date.
 * is_associated_with::Cannabidiol, a phytocannabinoid in is_associated_with::Cannabis.
 * is_associated_with::Efavirenz, an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT2A.
 * is_associated_with::Mefloquine, an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT2A and/or 5-HT2C receptors.
 * is_associated_with::Lisuride, an antiparkinson is_associated_with::dopamine agonist of the is_associated_with::ergoline class, that is also a dual 5-HT2A / 5-HT2C agonist and 5-HT2B antagonist.

Peripherally selective agonists
One effect of 5-HT2A receptor activation is a reduction in intraocular pressure, and so 5-HT2A agonists can be useful for the treatment of is_associated_with::glaucoma. This has led to the development of compounds such as is_associated_with::AL-34662 that are hoped to reduce pressure inside the eyes but without crossing the is_associated_with::blood–brain barrier and producing hallucinogenic side effects. Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30 mg/kg, although several of its more lipophilic analogues did produce the is_associated_with::head-twitch response known to be characteristic of hallucinogenic effects in rodents.

Silent antagonists

 * Although is_associated_with::ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, a few ergot derivatives such as is_associated_with::metergoline bind preferentially to members of the 5-HT2 receptor family.
 * The discovery of is_associated_with::Ketanserin was a landmark in the pharmacology of 5-HT2 receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well known antihypertensive action through 5-HT2 receptor family, but through its high affinity for alpha1 adrenergic receptors. It also has high affinity for H1 histaminergic receptors equal to that at 5-HT2A receptors. Compounds chemically related to ketanserin such as is_associated_with::ritanserin are more selective 5-HT2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT2A receptor antagonists, also potently inhibits 5-HT2C receptors.
 * is_associated_with::Nefazodone operates by blocking post-synaptic serotonin type-2A receptors and to a lesser extent by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake.
 * is_associated_with::Atypical antipsychotic drugs like is_associated_with::clozapine, is_associated_with::olanzapine, is_associated_with::quetiapine, is_associated_with::risperidone and is_associated_with::asenapine are relatively potent antagonists of 5-HT2A as are some of the lower potency old generation/typical antipsychotics. Other antagonists are is_associated_with::MDL-100,907 (prototype of another new series of 5-HT2Aantagonists) and is_associated_with::cyproheptadine.
 * is_associated_with::Pizotifen is a non-selective antagonist.
 * is_associated_with::LY-367,265 - dual 5-HT2A antagonist / SSRI with antidepressant effects
 * 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).
 * AMDA and related derivatives are another family of selective 5-HT2A antagonists.
 * is_associated_with::Hydroxyzine (Atarax)
 * is_associated_with::5-MeO-NBpBrT

Inverse agonists

 * is_associated_with::AC-90179 - potent and selective is_associated_with::inverse agonist at 5-HT2A, also 5-HT2C antagonist.
 * is_associated_with::Nelotanserin (APD-125) - selective 5-HT2A inverse agonist developed by is_associated_with::Arena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.
 * is_associated_with::Eplivanserin (is_associated_with::Sanofi Aventis), a sleeping pill that reached phase II trials (but for which the application for approval was withdrawn), acts as a selective 5-HT2A inverse agonist.
 * Pimavanserin (ACP-103) - more selective than AC-90179, orally active, antipsychotic in vivo, now in human clinical trials.
 * is_associated_with::Volinanserin

Functional selectivity
5-HT2A-receptor ligands may differentially activate the transductional pathways (see above). Studies evaluated the activation of two effectors, PLC and PLA2, by means of their is_associated_with::second messengers. Compounds displaying more pronounced is_associated_with::functional selectivity are 2,5-DMA and is_associated_with::2C-N. The former induces IP accumulation without activating the PLA2 mediated response, while the latter elicits AA release without activating the PLC mediated response.

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT2A agonists that produce headshakes in the is_associated_with::mouse and those that do not, such as is_associated_with::lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT2A agonists. One known example of differences in signal transduction is between the two 5-HT2A agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-is_associated_with::arrestins, more specifically is_associated_with::arrestin beta 2.

Role of lipophilicity
A set of ligands were evaluated. For agonists, a highly significant linear correlation was observed between binding affinity and is_associated_with::lipophilicity. For ligands exhibiting partial agonist or antagonist properties, the lipophilicity was consistently higher than would be expected for an agonist of comparable affinity.

Genetics
The 5-HT2A receptors is coded by the HTR2A gene. In humans the gene is located on is_associated_with::chromosome 13. The gene has previously been called just HTR2 until the description of two related genes is_associated_with::HTR2B and is_associated_with::HTR2C. Several interesting polymorphisms have been identified for HTR2A: is_associated_with::A-1438G (is_associated_with::rs6311), is_associated_with::C102T (is_associated_with::rs6313) and is_associated_with::His452Tyr (is_associated_with::rs6314). Many more polymorphisms exist for the gene. A 2006 paper listed 255.

Associations with psychiatric disorders
Several studies have seen links between the -1438G/A polymorphism and is_associated_with::mood disorders, such as is_associated_with::bipolar disorder and is_associated_with::major depressive disorder. A weak link with an is_associated_with::odds ratio of 1.3 has been found between the T102C polymorphism and is_associated_with::schizophrenia. This polymorphism has also been studied in relation to is_associated_with::suicide attempts, with a study finding excess of the C/C genotypes among the suicide attempters. A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.

These individual studies may, however, not give a full picture: A review from 2007 looking at the effect of different SNPs reported in separate studies stated that "genetic association studies &#91;of HTR2A gene variants with psychiatric disorders&#93; report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.

Treatment response
One study has found that genetic variations between individuals in the HTR2A gene may to some extent account for the difference in outcome of antidepressant treatment, so that patients suffering from is_associated_with::major depressive disorder and treated with is_associated_with::Citalopram may benefit more than others if they have one particular genotype. In this study 768 is_associated_with::single nucleotide polymorphism (SNP) across 68 genes were investigated and a SNP&mdash;termed is_associated_with::rs7997012&mdash;in the second is_associated_with::intron of the HTR2A gene showed significant association with treatment outcome.

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.

One study has also linked abnormal 5-HT2A polymorphisms which may enhance receptor activity with is_associated_with::Chronic Fatigue Syndrome.

Neuroimaging
The 5-HT2A receptors may be imaged with is_associated_with::PET-scanners using the fluorine-18-is_associated_with::altanserin and MDL 100,907 is_associated_with::radioligands that binds to the neuroreceptor, e.g., one study reported a reduced binding of altanserin particularly in the is_associated_with::hippocampus in patients with is_associated_with::major depressive disorder. Another PET study reported increased altanserin binding in the caudate nuclei in is_associated_with::obsessive compulsive disorder patients compared to a healthy control group.

Patients with is_associated_with::Tourette's syndrome have also been scanned and the study found an increased binding of altanserin for patients compared to healthy controls. The altanserin uptake decreases with age reflecting a loss of specific 5-HT2A receptors with age. A study has also found a positive correlation among healthy subjects between altanserin binding and the personality trait is_associated_with::neuroticism as measured by the is_associated_with::NEO PI-R personality questionnaire.

Role in virus endocytosis
5-HT2A may be a necessary receptor for is_associated_with::clathrin mediated is_associated_with::endocytosis of the human is_associated_with::polyoma virus called is_associated_with::JC virus, the causative agent of is_associated_with::progressive multifocal leukoencephalopathy (PML), that enters cells such as is_associated_with::oligodendrocytes, is_associated_with::astrocytes, is_associated_with::B lymphocytes, and kidney epithelial cells. These cells need to express both the alpha 2-6–linked is_associated_with::sialic acid component of the 5-HT2A receptor in order to endocytose JCV.