The serotonin 1A receptor (or 5-HT_1A receptor) is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

. 5-HT1A is expressed in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

, spleen, and neonatal

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

Distribution

The 5-HT_1A receptor is the most widespread of all the 5-HT receptors. In the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, 5-HT_1A receptors exist in the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

septum In biology, a septum (Latin language, Latin for ''something that encloses''; septa) is a wall, dividing a Body cavity, cavity or structure into smaller ones. A cavity or structure divided in this way may be referred to as septate. Examples Hum ...

, amygdala, and raphe nucleus in high densities, while low amounts also exist in the basal ganglia and

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

. The 5-HT_1A receptors in the raphe nucleus are largely somatodendritic autoreceptors, whereas those in other areas such as the hippocampus are postsynaptic receptors.

Function

Neuromodulation

5-HT_1A receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s are involved in neuromodulation. They decrease

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

and heart rate via a central mechanism, by inducing peripheral vasodilation, and by stimulating the

vagus nerve The vagus nerve, also known as the tenth cranial nerve (CN X), plays a crucial role in the autonomic nervous system, which is responsible for regulating involuntary functions within the human body. This nerve carries both sensory and motor fibe ...

. These effects are the result of activation of 5-HT_1A receptors within the rostral ventrolateral medulla. The sympatholytic antihypertensive

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

urapidil is an α₁-adrenergic receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Vasodilation of the

blood vessel Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...

s in the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

via central 5-HT_1A activation increases heat dissipation from the organism out into the environment, causing a decrease in body temperature. Activation of central 5-HT_1A receptors triggers the release or inhibition of norepinephrine depending on species, presumably from the locus coeruleus, which then reduces or increases neuronal tone to the iris sphincter muscle by modulation of postsynaptic α₂-adrenergic receptors within the Edinger-Westphal nucleus, resulting in pupil dilation in

rodent Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...

s, and pupil constriction in

primate Primates is an order (biology), order of mammals, which is further divided into the Strepsirrhini, strepsirrhines, which include lemurs, galagos, and Lorisidae, lorisids; and the Haplorhini, haplorhines, which include Tarsiiformes, tarsiers a ...

s including

human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

s. 5-HT_1A receptor agonists like

buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

and flesinoxan show efficacy in relieving

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

and depression. Buspirone and tandospirone are currently approved for these indications in different parts of the world. Others such as gepirone, flesinoxan, flibanserin, and naluzotan have also been investigated, though none have been fully developed and approved yet. Some of the atypical antipsychotics like lurasidone and aripiprazole are also

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

s at the 5-HT_1A receptor and are sometimes used in low doses as augmentations to standard

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

s like the selective serotonin reuptake inhibitors (SSRIs). Mice lacking 5-HT_1A receptors altogether ( knockout) show increased anxiety but lower depressive-like behaviour. 5-HT_1A autoreceptor desensitization and increased 5-HT_1A receptor postsynaptic activation via general increases in serotonin levels by serotonin precursor supplementation, serotonin reuptake inhibition, or inhibition of

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

has been shown to be a major mediator in the therapeutic benefits of most mainstream

supplements and pharmaceuticals, including serotonin precursors like L-tryptophan and 5-HTP, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs),

tetracyclic antidepressant Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their tetracyclic chemical structure, containing four cyclic compound, rings of atoms, and are closely related to th ...

s (TeCAs), and monoamine oxidase inhibitors (MAOIs). 5-HT_1A receptor activation likely plays a significant role in the positive effects of serotonin releasing agents (SRAs) like MDMA (commonly known as ecstasy) as well. 5-HT_1A receptors in the dorsal raphe nucleus are co-localized with neurokinin 1 (NK₁) receptors and have been shown to inhibit the release of substance P, their endogenous

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

. In addition to being

and anxiolytic in effect, 5-HT_1A receptor activation has also been demonstrated to be antiemetic and 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

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and emesis, and are also being investigated for the treatment of anxiety and depression. 5-HT_1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and

, and may be useful for improving the symptoms of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. As mentioned above, some of the atypical antipsychotics are 5-HT_1A 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 as seen upon postsynaptic activation of the 5-HT_1A receptor. The activation of 5-HT_1A receptors has been demonstrated to impair certain aspects of

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

(affecting declarative and non-declarative memory functions) and

learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, Attitude (psychology), attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and ...

(due to interference with memory-encoding mechanisms), by inhibiting the release of

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

and

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

in various areas of the

. 5-HT_1A activation is known to improve cognitive functions associated with the prefrontal cortex, possibly via inducing prefrontal cortex dopamine and acetylcholine release. Conversely, the 5-HT_1A antagonist, WAY100635, alleviated learning and memory impairments induced by

blockade (with dizocilpine) or hippocampal cholinergic denervation (by fornix transection) in primates. Furthermore, 5-HT_1A receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.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

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. Other effects of 5-HT_1A activation that have been observed in scientific research include: * Decreased aggression * Increased sociability * Decreased impulsivity * Inhibition of drug-seeking behavior * Facilitation of sex drive and arousal * Inhibition of penile erection * Diminished food intake * Prolongation of REM

sleep Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...

latency * Reversal of opioid-induced respiratory depression

Endocrinology

5-HT_1A receptor activation induces the secretion of various

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s including cortisol, corticosterone, adrenocorticotropic hormone (ACTH),

oxytocin Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...

, prolactin, growth hormone, and β-endorphin. The receptor does not affect vasopressin or 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-HT_1A receptors can be located on the cell body, dendrites,

axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...

s, and both presynaptically and postsynaptically in nerve terminals or synapses. Those located on the soma and dendrites are referred to as 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 autoreceptors; they typically constitute the key component of an ultra-short

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...

loop whereby the neuron's release of neurotransmitter inhibits its further release of neurotransmitter. Stimulation of 5-HT_1A autoreceptors inhibits the release of serotonin in nerve terminals. For this reason, 5-HT_1A receptor agonists tend to exert a biphasic mode of action; they decrease serotonin release and postsynaptic 5-HT_1A receptor activity in low doses, and further decrease serotonin release but increase postsynaptic 5-HT_1A 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 desensitize 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, serotonin reuptake inhibitors that also have 5-HT_1A receptor antagonistic or partial agonistic properties, such as vilazodone and 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 fenfluramine and MDMA bypass serotonin autoreceptors such as 5-HT_1A. 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. [Note: This is questionable as the level of serotonin output from SRAs is still dose dependant and, while SRAs will initially bypass autoreceptors, the increase in serotonin they induce will then agonise autoreceptors.] In contrast to SRAs, SSRIs may decrease serotonin levels initially (especially at lower dosages due to the biphasic mode of action mentioned above) and require several weeks of chronic dosing before serotonin concentrations reach their maximal elevation (due to 1A autoreceptor desensitization) and full clinical benefits for conditions such as depression and anxiety are seen (although other studies show an acute increase in 5-HT which may account for initial worsening of symptoms in sensitive individuals). For these reasons, selective serotonin releasing agents (SSRAs) such as MDAI and 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-HT_1A receptor agonists also bypass the 5-HT_1A autoreceptor-mediated inhibition of serotonin release and therefore increase 5-HT_1A postsynaptic receptor activation by directly agonizing the postsynaptic receptors in lieu of serotonin.

Ligands

The distribution of 5-HT_1A receptors in the

human brain The human brain is the central organ (anatomy), organ of the nervous system, and with the spinal cord, comprises the central nervous system. It consists of the cerebrum, the brainstem and the cerebellum. The brain controls most of the activi ...

may be imaged with the positron emission tomography using the radioligand sup>11C WAY-100,635. For example, one study has found increased 5-HT_1A binding in type 2 diabetes. Another PET study found a negative correlation between the amount of 5-HT_1A binding in the raphe nuclei,

and

neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...

and a self-reported tendency to have spiritual experiences. Labeled with tritium, WAY-100,635 may also be used in autoradiography.

Agonists

Partial agonists

* 2C-B * 2C-E * 2C-T-2 * 4C-T-2 * 5-CT * 5-MT * 5-MeO-DiPT * 5-MeO-DMT * 5-MeO-MiPT * 5-MeO-TMT * 6-F-DMT * Adatanserin * αET *

Amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

* αMT * Aripiprazole * Asenapine * Bacoside * Bay R 1531 * Befiradol * Binospirone * Brexpiprazole * Bufotenin *

Buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

(postsynaptic 5-HT_1A) *

Cannabidiol Cannabidiol (CBD) is a phytocannabinoid, one of 113 identified cannabinoids in ''Cannabis'', along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. Medically, it is an anticonvulsant used to treat multiple f ...

* Cariprazine * Clozapine * ''cis''-LSZ * Dihydroergotamine * Dimethyltryptamine * DiPT * DOET * DOI * DPT * Ebalzotan * Eltoprazine * EMDT * Ergotamine * Etoperidone * F-11,461 * F-12,826 * F-13,714 * F-14,679 * Flesinoxan * Flibanserin * Ginkgo biloba * Gepirone * Haloperidol * Lamotrigine * Ipsapirone * Limonene * Lisuride * Lurasidone * LY-301,317 * Lysergic acid diethylamide (LSD) *

Mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

* 3,4-Methylenedioxyamphetamine (MDA) * 3,4-Methylenedioxymethamphetamine (MDMA) *

Methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

* Methysergide * Naluzotan * NBUMP * Nefazodone * Olanzapine * Osemozotan (postsynaptic 5-HT_1A) * Perospirone * Pyrimidinylpiperazine * Piclozotan * Psilocin * Psilocybin * Quetiapine * Rauwolscine * Roxindole * RR-2B * RU-24,969 * S-15,535 * Sarizotan * SS-2C * SSR-181,507 * Sunepitron * Tandospirone * Tiospirone * Trazodone * Trifluoromethylphenylpiperazine * Trimethoxyamphetamine * Umespirone * Urapidil * Vilazodone * Vortioxetine * Xaliproden * Yohimbine * Zalospirone * Ziprasidone

Full agonists

8-OH-DPAT 8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor, 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonis ...

A-74283
* Alnespirone *

(presynaptic 5-HT_1A) * Befiradol * Tetrahydrocannabivarin (THCV) * Eptapirone * Lesopitron * MKC-242 * LY-293,284 * Osemozotan (presynaptic 5-HT_1A) * Repinotan * U-92,016-A * Flibanserin * Vortioxetine

Biased agonists

* HBK-17 – β-arrestin biased agonist * NLX-204 – ERK1/ 2 preferring agonist * F-15,599, also known as NLX-101

Antagonists

* Alprenolol * AV-965 * Binospirone (postsynaptic 5-HT_1A) * BMY-7,378 * Cannabigerol * Cyanopindolol * Cyproheptadine * Dotarizine * Flopropione * GR-46,611 * Iodocyanopindolol * Isamoltane * Lecozotan * Mefway * Methiothepin * MPPF * NAN-190 * Nebivolol * Oxprenolol * Pindobind * Pindolol (presynaptic 5-HT_1A) * Propranolol * Risperidone (weak) * Robalzotan * SB-649,915 * SDZ-216,525 * Spiperone * Spiramide * Spiroxatrine * UH-301 * WAY-100,135 * WAY-100,635 * Xylamidine

Allosteric modulators

Cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

– endogenous PAM * Oleamide – endogenous PAM * Zn²⁺ – endogenous NAM * AM-2201 – exogenous PAM

Genetics

The 5-HT_1A receptor is coded by the ''HTR1A''

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

Protein-protein interactions

The 5-HT_1A receptor has been shown to interact with brain-derived neurotrophic factor (BDNF), which may play a major role in its regulation of mood and anxiety.

Receptor oligomers

The 5-HT_1A receptor forms heterodimers with the following receptors: 5-HT₇, 5-HT_1B, 5-HT_1D, GABA_B2, LPA₁ (GPCR26), LPA₃, S1P₁, S1P₃.

References

External links

* * {{DEFAULTSORT:5-Ht1a Receptor Serotonin receptors