5-HT1A receptor

The 5-HT1A receptor is a subtype of is_associated_with::5-HT receptor that binds the is_associated_with::endogenous is_associated_with::neurotransmitter is_associated_with::serotonin (5-hydroxytryptamine, 5-HT). It is a is_associated_with::G protein-coupled receptor (GPCR) that is coupled to Gi/Go and mediates inhibitory is_associated_with::neurotransmission. HTR1A denotes the is_associated_with::human is_associated_with::gene encoding for the receptor.

Distribution
The 5-HT1A receptor is the most widespread of all the 5-HT receptors. In the is_associated_with::central nervous system, 5-HT1A receptors exist in the is_associated_with::cerebral cortex, is_associated_with::hippocampus, septum, is_associated_with::amygdala, and raphe nucleus in high densities, while low amounts also exist in the is_associated_with::basal ganglia and is_associated_with::thalamus. The 5-HT1A receptors in the raphe nucleus are largely is_associated_with::somatodendritic is_associated_with::autoreceptors, whereas those in other areas such as the hippocampus are is_associated_with::postsynaptic receptors.

Neuromodulation
5-HT1A receptor is_associated_with::agonists are involved in neuromodulation. They decrease is_associated_with::blood pressure and is_associated_with::heart rate via a central mechanism, by inducing is_associated_with::peripheral is_associated_with::vasodilation, and by stimulating the is_associated_with::vagus nerve. These effects are the result of activation of 5-HT1A receptors within the is_associated_with::rostral ventrolateral medulla. The is_associated_with::sympatholytic is_associated_with::antihypertensive is_associated_with::drug is_associated_with::urapidil is an α1-adrenergic receptor antagonist and α2-adrenergic receptor agonist, as well as 5-HT1A receptor agonist, and it has been demonstrated that the latter property contributes to its overall therapeutic effects. Vasodilation of the is_associated_with::blood vessels in the is_associated_with::skin via central 5-HT1A activation increases is_associated_with::heat dissipation from the organism out into the environment, causing a decrease in is_associated_with::body temperature.

Activation of central 5-HT1A receptors triggers the release or inhibition of is_associated_with::norepinephrine depending on species, presumably from the is_associated_with::locus coeruleus, which then reduces or increases neuronal tone to the is_associated_with::iris sphincter muscle by modulation of is_associated_with::postsynaptic α2-adrenergic receptors within the is_associated_with::Edinger-Westphal nucleus, resulting in pupil dilation in is_associated_with::rodents, and pupil constriction in is_associated_with::primates including is_associated_with::humans.

5-HT1A receptor agonists like is_associated_with::buspirone and is_associated_with::flesinoxan show efficacy in relieving is_associated_with::anxiety and depression, and is_associated_with::buspirone and is_associated_with::tandospirone are currently approved for these indications in various parts of the world. Others such as is_associated_with::gepirone, is_associated_with::flesinoxan, is_associated_with::flibanserin, and is_associated_with::naluzotan have also been investigated, though none have been fully developed and approved yet. Some of the is_associated_with::atypical antipsychotics like is_associated_with::aripiprazole are also is_associated_with::partial agonists at the 5-HT1A receptor and are sometimes used in low doses as augmentations to standard is_associated_with::antidepressants like the is_associated_with::selective serotonin reuptake inhibitors (SSRIs).

5-HT1A autoreceptor desensitization and increased 5-HT1A receptor postsynaptic activation via general increases in serotonin levels by serotonin precursor supplementation, serotonin reuptake inhibition, or is_associated_with::monoamine oxidase inhibition has been shown to be a major mediator in the therapeutic benefits of most mainstream is_associated_with::antidepressant supplements and is_associated_with::pharmaceuticals, including serotonin precursors like is_associated_with::L-tryptophan and 5-HTP, is_associated_with::selective serotonin reuptake inhibitors (SSRIs), is_associated_with::serotonin-norepinephrine reuptake inhibitors (SNRIs), is_associated_with::tricyclic antidepressants (TCAs), is_associated_with::tetracyclic antidepressants (TeCAs), and is_associated_with::monoamine oxidase inhibitors (MAOIs). 5-HT1A receptor activation likely plays a significant role in the positive effects of serotonin is_associated_with::releasing agents (SRAs) like is_associated_with::MDMA ("Ecstasy") as well.

5-HT1A receptors in the is_associated_with::dorsal raphe nucleus are co-localized with neurokinin 1 (NK1) receptors and have been shown to inhibit the release of is_associated_with::substance P, their is_associated_with::endogenous is_associated_with::ligand. In addition to being is_associated_with::antidepressant and is_associated_with::anxiolytic in effect, 5-HT1A receptor activation has also been demonstrated to be is_associated_with::antiemetic and is_associated_with::analgesic,  and all of these properties may be mediated in part or full, depending on the property in question, by NK1 receptor inhibition. Consequently, novel NK1 receptor antagonists are now in use for the treatment of is_associated_with::nausea and is_associated_with::emesis, and are also being investigated for the treatment of is_associated_with::anxiety and depression.

5-HT1A receptor activation has been shown to increase is_associated_with::dopamine release in the is_associated_with::medial prefrontal cortex, is_associated_with::striatum, and is_associated_with::hippocampus, and may be useful for improving the symptoms of is_associated_with::schizophrenia and is_associated_with::Parkinson's disease. As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy. Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects seen upon postsynaptic activation of the 5-HT1A receptor.

Activation of 5-HT1A receptors has been demonstrated to impair certain aspects of is_associated_with::memory (affecting declarative and non-declarative memory functions) and is_associated_with::learning (due to interference with memory-encoding mechanisms), by inhibiting the release of is_associated_with::glutamate and is_associated_with::acetylcholine in various areas of the is_associated_with::brain. 5-HT1A activation are known to improve cognitive functions associated with the prefrontal cortex, possibly via inducing prefrontal cortex dopamine and acetylcholine release. Conversely, 5-HT1A receptor is_associated_with::antagonists such as is_associated_with::lecozotan have been shown to facilitate certain types of learning and memory in rodents, and as a result, are being developed as novel treatments for is_associated_with::Alzheimer's disease.

Other effects of 5-HT1A activation that have been observed in scientific research include:


 * Decreased is_associated_with::aggression
 * Increased sociability
 * Decreased is_associated_with::impulsivity
 * Inhibition of drug-seeking behavior
 * Facilitation of sex drive and arousal
 * Inhibition of is_associated_with::penile erection
 * Diminished food intake
 * Prolongation of REM is_associated_with::sleep latency
 * Reversal of is_associated_with::opioid-induced is_associated_with::respiratory depression.

Endocrinology
5-HT1A receptor activation induces the is_associated_with::secretion of various is_associated_with::hormones including is_associated_with::cortisol, is_associated_with::corticosterone, is_associated_with::adrenocorticotropic hormone (ACTH), is_associated_with::oxytocin, is_associated_with::prolactin, is_associated_with::growth hormone, and is_associated_with::β-endorphin. The receptor does not affect is_associated_with::vasopressin or is_associated_with::renin secretion, unlike the 5-HT2 receptors. It has been suggested that oxytocin release may contribute to the prosocial, antiaggressive, and anxiolytic properties observed upon activation of the receptor. β-Endorphin secretion may contribute to antidepressant, anxiolytic, and analgesic effects.

Autoreceptors
5-HT1A receptors can be located on the is_associated_with::cell body, is_associated_with::dendrites, is_associated_with::axons, and both is_associated_with::presynaptically and is_associated_with::postsynaptically in is_associated_with::nerve terminals or is_associated_with::synapses. Those located on the soma and dendrites are referred to as is_associated_with::somatodendritic, and those located presynaptically in the synapse are simply referred to as presynaptic. As a group, receptors that are sensitive to the neurotransmitter that is released by the neuron on which the receptors are located are known as is_associated_with::autoreceptors; they typically constitute the key component of an ultra-short negative feedback loop whereby the neuron's release of neurotransmitter inhibits its further release of neurotransmitter. Stimulation of 5-HT1A autoreceptors inhibits the release of serotonin in nerve terminals. For this reason, 5-HT1A receptor agonists tend to exert a biphasic mode of action; they decrease serotonin release and postsynaptic 5-HT1A receptor activity in low doses, and further decrease serotonin release but increase postsynaptic 5-HT1A receptor activity at higher doses by directly stimulating the receptors in place of serotonin.

This autoreceptor-mediated inhibition of serotonin release has been theorized to be a major factor in the therapeutic lag that is seen with serotonergic antidepressants such as the SSRIs. The autoreceptors must first densensitize before the concentration of extracellular serotonin in the synapse can become elevated appreciably. Though the responsiveness of the autoreceptors is somewhat reduced with chronic treatment, they still remain effective at constraining large increases in extracellular serotonin concentrations. For this reason, is_associated_with::serotonin reuptake inhibitors that also have 5-HT1A receptor antagonistic or partial agonistic properties, such as is_associated_with::vilazodone and is_associated_with::SB-649,915, are being investigated and introduced as novel antidepressants with the potential for a faster onset of action and improved effectiveness compared to those currently available.

Unlike most drugs that elevate extracellular serotonin levels like the SSRIs and MAOIs, SRAs such as is_associated_with::fenfluramine and is_associated_with::MDMA bypass serotonin autoreceptors such as 5-HT1A. They do this by directly acting on the release mechanisms of serotonin neurons and forcing release to occur regardless of autoreceptor-mediated inhibition. As such, SRAs induce immediate and much greater increases in extracellular serotonin concentrations compared to other serotonin-elevating agents such as the SSRIs. In contrast to SRAs, SSRIs actually decrease serotonin levels initially and require several weeks of chronic dosing before serotonin concentrations reach their maximal elevation and full clinical benefits for conditions such as depression and anxiety are seen. For these reasons, is_associated_with::selective serotonin releasing agents (SSRAs) such as is_associated_with::MDAI and is_associated_with::MMAI have been proposed as novel antidepressants with a putatively faster onset of action and improved effectiveness compared to current treatments.

Similarly to SRAs, sufficiently high doses of 5-HT1A receptor agonists also bypass the 5-HT1A autoreceptor-mediated inhibition of serotonin release and therefore increase 5-HT1A postsynaptic receptor activation by directly agonizing the postsynaptic receptors is_associated_with::in lieu of serotonin. However, in contrast to SRAs, 5-HT1A receptor agonists do not bypass the inhibitory effect of 5-HT1A receptors located as is_associated_with::heteroreceptors in non-is_associated_with::serotonergic is_associated_with::synapses where 5-HT1A postsynaptic receptors are not present, which, instead of serotonin, modulate the release of other is_associated_with::neurotransmitters such as is_associated_with::dopamine or is_associated_with::glutamate. The therapeutic consequences of this difference, if any, are unknown.

Ligands
The distribution of 5-HT1A receptors in the is_associated_with::human brain may be imaged with the is_associated_with::positron emission tomography using the is_associated_with::radioligand [11C]is_associated_with::WAY-100,635. For example, one study has found increased 5-HT1A binding in type 2 is_associated_with::diabetes. Another PET study found a negative correlation between the amount of 5-HT1A binding in the is_associated_with::raphe nuclei, is_associated_with::hippocampus and is_associated_with::neocortex and a self-reported tendency to have is_associated_with::spiritual experiences. Labeled with is_associated_with::tritium, WAY-100,635 may also be used in is_associated_with::autoradiography.

Partial agonists

 * 5-CT
 * 5-MT
 * is_associated_with::5-MeO-DMT
 * is_associated_with::Adatanserin
 * αET
 * is_associated_with::Amphetamine
 * αMT
 * is_associated_with::Aripiprazole
 * is_associated_with::Asenapine
 * is_associated_with::Bay R 1531
 * is_associated_with::Befiradol
 * is_associated_with::Binospirone
 * is_associated_with::Bufotenin
 * is_associated_with::Buspirone
 * is_associated_with::Cannabidiol
 * is_associated_with::Clozapine
 * is_associated_with::Dihydroergotamine
 * is_associated_with::Ebalzotan
 * is_associated_with::Eltoprazine
 * is_associated_with::Ergotamine
 * is_associated_with::Etoperidone
 * is_associated_with::F-11,461
 * is_associated_with::F-12,826
 * is_associated_with::F-13,714
 * is_associated_with::F-14,679
 * is_associated_with::Flesinoxan
 * is_associated_with::Flibanserin
 * is_associated_with::Ginkgo Biloba
 * is_associated_with::Gepirone
 * is_associated_with::Haloperidol
 * is_associated_with::Ipsapirone
 * is_associated_with::Lisuride
 * is_associated_with::Lurasidone
 * is_associated_with::LY-301,317
 * Lysergic Acid Diethylamide (LSD)
 * is_associated_with::MDMA
 * is_associated_with::Naluzotan
 * is_associated_with::NBUMP
 * is_associated_with::Nefazodone
 * is_associated_with::Olanzapine
 * is_associated_with::Perospirone
 * is_associated_with::Piclozotan
 * is_associated_with::Psilocin
 * is_associated_with::Psilocybin
 * is_associated_with::Quetiapine
 * is_associated_with::Rauwolscine
 * is_associated_with::RU-24,969
 * is_associated_with::S-15,535
 * is_associated_with::Sarizotan
 * is_associated_with::SSR-181,507
 * is_associated_with::Sunepitron
 * is_associated_with::Tandospirone
 * is_associated_with::Tiospirone
 * is_associated_with::Trazodone
 * is_associated_with::Trifluoromethylphenylpiperazine
 * is_associated_with::Urapidil
 * is_associated_with::Vortioxetine
 * is_associated_with::Vilazodone
 * is_associated_with::Xaliproden
 * is_associated_with::Yohimbine
 * is_associated_with::Zalospirone
 * is_associated_with::Ziprasidone

Full agonists

 * is_associated_with::8-OH-DPAT
 * is_associated_with::Alnespirone
 * is_associated_with::Befiradol
 * is_associated_with::Eptapirone
 * is_associated_with::F-15,599
 * is_associated_with::Lesopitron
 * is_associated_with::MKC-242
 * is_associated_with::LY-293,284
 * is_associated_with::Osemozotan (partial at postsynaptic receptors)
 * is_associated_with::Repinotan
 * is_associated_with::U-92,016-A

Antagonists

 * is_associated_with::Alprenolol
 * is_associated_with::AV-965
 * is_associated_with::BMY-7,378
 * is_associated_with::Cyanopindolol
 * is_associated_with::Dotarizine
 * is_associated_with::Flopropione
 * is_associated_with::GR-46,611
 * is_associated_with::Iodocyanopindolol
 * is_associated_with::Isamoltane
 * is_associated_with::Lecozotan
 * is_associated_with::Methiothepin
 * is_associated_with::Methysergide
 * is_associated_with::MPPF
 * is_associated_with::NAN-190
 * is_associated_with::Oxprenolol
 * is_associated_with::Pindobind
 * is_associated_with::Pindolol
 * is_associated_with::Propranolol
 * is_associated_with::Risperidone
 * is_associated_with::Robalzotan
 * is_associated_with::SB-649,915
 * is_associated_with::SDZ-216,525
 * is_associated_with::Spiperone
 * is_associated_with::Spiramide
 * is_associated_with::Spiroxatrine
 * is_associated_with::UH-301
 * is_associated_with::WAY-100,135
 * is_associated_with::WAY-100,635
 * is_associated_with::Xylamidine
 * is_associated_with::Mefway

Genetics
The 5-HT1A receptor is coded by the HTR1A is_associated_with::gene. There are several human polymorphisms associated with this gene. A 2007 review listed 27 is_associated_with::single nucleotide polymorphisms (SNP). The most investigated SNPs are C-1019G (is_associated_with::rs6295), C-1018G, Ile28Val (is_associated_with::rs1799921), Arg219Leu (is_associated_with::rs1800044), and Gly22Ser (is_associated_with::rs1799920). Some of the other SNPs are Pro16Leu, Gly272Asp, and the is_associated_with::synonymous polymorphism G294A (is_associated_with::rs6294). These gene variants have been studied in relation to is_associated_with::psychiatric disorders with no definitive results.

Protein-protein interactions
The 5-HT1A receptor has been shown to interact with is_associated_with::brain-derived neurotrophic factor (BDNF), which may play a major role in its regulation of mood and anxiety.

Receptor oligomers
The 5-HT1A receptor forms heterodimers with the following receptors: 5-HT7, 5-HT1B, 5-HT1D, GABAB2, GPCR26, LPA1, LPA3, S1P1, S1P3.