5-HT1A receptor
Encyclopedia
The 5-HT1A receptor is a subtype of 5-HT receptor
that binds the endogenous
neurotransmitter
serotonin
(5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor
(GPCR) that is coupled to Gi/Go
and mediates inhibitory neurotransmission
. HTR1A denotes the human
gene
encoding for the receptor
.
, 5-HT1A receptors exist in the cerebral cortex
, hippocampus
, septum
, amygdala
, and raphe nucleus
in high densities, while low amounts also exist in the basal ganglia
and thalamus
. The 5-HT1A receptors in the raphe nucleus are largely somatodendritic autoreceptor
s, whereas those in other areas such as the hippocampus are postsynaptic receptors.
agonist
s decrease blood pressure
and heart rate
via a central mechanism, by inducing peripheral
vasodilation
, and by stimulating the vagus nerve
. These effects are the result of activation of 5-HT1A receptors within the rostral ventrolateral medulla
. The sympatholytic
antihypertensive
drug
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 blood vessel
s in the skin
via central 5-HT1A activation increases heat
dissipation
from the organism out into the environment, causing a decrease in body temperature.
Activation of central 5-HT1A 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
s, and pupil constriction
in primate
s including human
s.
5-HT1A receptor agonists like buspirone
and flesinoxan
show efficacy in relieving anxiety
and depression
, and buspirone
and tandospirone
are currently approved for these indications in various parts of the world. Others such as gepirone
, flesinoxan
, flibanserin
, and PRX-00023
have also been investigated, though none have been fully developed and approved as of yet. Some of the atypical antipsychotic
s like aripiprazole
are also partial agonist
s at the 5-HT1A receptor and are sometimes used in low doses as augmentations to standard antidepressant
s like the selective serotonin reuptake inhibitor
s (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 monoamine oxidase
inhibition has been shown to be a major mediator in the therapeutic benefits of most mainstream antidepressant
supplement
s and pharmaceuticals, including serotonin precursors like L-tryptophan and 5-HTP
, selective serotonin reuptake inhibitor
s (SSRIs), serotonin-norepinephrine reuptake inhibitor
s (SNRIs), tricyclic antidepressant
s (TCAs), tetracyclic antidepressant
s (TeCAs), and monoamine oxidase inhibitor
s (MAOIs). 5-HT1A receptor activation likely plays a significant role in the positive effects of serotonin releasing agent
s (SRAs) like MDMA ("Ecstasy") as well.
5-HT1A 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 addition to being antidepressant
and anxiolytic
in effect, 5-HT1A 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
and emesis, and are also being investigated for the treatment of anxiety
and depression
.
5-HT1A receptor activation has been shown to increase dopamine
release in the medial prefrontal cortex, striatum
, and hippocampus
, and may be useful for improving the symptoms of schizophrenia
and 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 cognition
, learning
, and memory
by inhibiting the release of glutamate and acetylcholine
in various areas of the brain
. Conversely, 5-HT1A receptor antagonist
s such as 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
.
Other effects of 5-HT1A activation include decreased aggression
or increased serenic behavior, increased sociability, decreased impulsivity
, inhibition of addictive
behavior, facilitation of sexual behavior and arousal
, inhibition of penile erection, decreased food intake or anorexia
, prolongation of REM sleep
latency, and enhanced breathing
or hyperventilation
and reversal of opioid
-induced respiratory depression.
of various hormone
s including cortisol
, corticosterone
, adrenocorticotropic hormone
(ACTH), oxytocin
, prolactin
, growth hormone
, and β-endorphin. The receptor does not affect vasopressin
or renin
secretion, unlike the 5-HT2 receptor
s. It has been suggested that oxytocin release may contribute to the prosocial, antiaggressive or serenic, and anxiolytic properties observed upon activation of the receptor. β-Endorphin secretion likely contributes to antidepressant, anxiolytic, and analgesic effects.
, dendrite
s, axon
s, and both presynaptically and postsynaptically in nerve terminals or synapse
s. Those located on the soma and dendrites are called somatodendritic, and those located presynaptically in the synapse are aptly titled presynaptic. As a group, they are known as autoreceptor
s. 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 moderate to high doses by directly stimulating the receptors in replacement of serotonin.
This autoreceptor-mediated inhibition of serotonin release has been postulated to be one of the reasons for the therapeutic lag that is commonly reported for most mainstream 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, serotonin reuptake inhibitors that also have 5-HT1A receptor antagonistic or partial agonistic properties such as vilazodone
and SB-649,915
are currently being investigated as novel antidepressants with a faster onset of action and greater efficacy than many of those currently available.
Unlike most drugs that elevate extracellular serotonin levels like the SSRIs and MAOIs, SRAs such as fenfluramine
and MDMA ("Ecstasy") fully bypass serotonin autoreceptors like 5-HT1A by forcing release to occur regardless of their inhibition. This is why SRAs display immediate and full effects in contrast to drugs like the SSRIs, which require several weeks of chronic dosing before therapeutic benefits are seen, and also why SRAs are much stronger than SSRIs and related compounds in effect, as they produce far more robust and balanced increases in extracellular serotonin concentrations. For these reasons, selective serotonin releasing agent
s (SSRAs), including MDAI, MMAI, and 4-MTA, have been proposed as novel antidepressants with an immediate onset of action and far greater efficacy in comparison to most current treatments.
Sufficient doses of 5-HT1A receptor agonists themselves, like SRAs, are capable of fully bypassing the 5-HT1A autoreceptor-mediated inhibition of serotonin release, and therefore decreased 5-HT1A postsynaptic receptor activation as well, by directly agonizing the postsynaptic receptors in lieu of serotonin. It is important to note however, that unlike SRAs, 5-HT1A receptor agonists are incapable of bypassing the inhibitory effect of 5-HT1A autoreceptors located as heteroreceptor
s in non-serotonergic
synapse
s where 5-HT1A postsynaptic receptors are not present, which instead of serotonin, modulate the release of other neurotransmitter
s such as dopamine
or glutamate.
may be imaged with the positron emission tomography
using the radioligand
[11C]WAY-100,635.
For example, one study has found increased 5-HT1A binding in type 2 diabetes. Another PET study found a negative correlation between the amount of 5-HT1A binding in the raphe nuclei
, hippocampus
and neocortex
and a self-reported tendency to have spiritual experiences. Labeled with tritium
, WAY-100,635 may also be used in autoradiography.
. There are several human polymorphism
s associated with this gene. A 2007 review listed 27 single nucleotide polymorphism
s (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.
with brain-derived neurotrophic factor
(BDNF), which may play a major role in its regulation of mood and anxiety. It has also been shown to interact with sphingosine-1-phosphate receptor 1 (S1PR1).
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
that binds the endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
(GPCR) that is coupled to Gi/Go
Gi alpha subunit
Gi alpha subunit is a heterotrimeric G protein subunit that inhibits the production of cAMP from ATP.- Receptors :The following G protein-coupled receptors couple to the Gi subunit:* Acetylcholine M2 & M4 receptors...
and mediates inhibitory neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
. HTR1A denotes the human
Human
Humans are the only living species in the Homo genus...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encoding for the receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
.
Distribution
The 5-HT1A receptor is the most widespread of all the 5-HT receptors. In the central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, 5-HT1A receptors exist in the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, septum
Septum pellucidum
The septum pellucidum , and not to be confused with the medial septum, is a thin, triangular, vertical membrane separating the anterior horns of the left and right lateral ventricles of the brain...
, amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, and raphe nucleus
Raphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...
in high densities, while low amounts also exist in the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
and thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
. The 5-HT1A receptors in the raphe nucleus are largely somatodendritic autoreceptor
Autoreceptor
An autoreceptor is a receptor located on presynaptic nerve cell membranes and serves as a part of a feedback loop in signal transduction. It is sensitive only to those neurotransmitters or hormones that are released by the neuron in whose membrane the autoreceptor sits.Canonically, a presynaptic...
s, whereas those in other areas such as the hippocampus are postsynaptic receptors.
Neuromodulation
5-HT1A receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s decrease blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
and heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
via a central mechanism, by inducing peripheral
Peripheral
A peripheral is a device attached to a host computer, but not part of it, and is more or less dependent on the host. It expands the host's capabilities, but does not form part of the core computer architecture....
vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
, and by stimulating the vagus nerve
Vagus nerve
The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
. These effects are the result of activation of 5-HT1A receptors within the rostral ventrolateral medulla
Rostral ventrolateral medulla
Control of blood pressure is crucially dependent on the integrity of a small region of the brainstem called the ventrolateral medulla. Within this part of the brain are the cells that control the heart, blood vessels, swallowing, breathing and many other functions of the body that are not noticed...
. The sympatholytic
Sympatholytic
A sympatholytic drug is a medication which inhibits the postganglionic functioning of the sympathetic nervous system . They are indicated for various functions, for example they may be used as antihypertensives...
antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
urapidil
Urapidil
Urapidil is a sympatholytic antihypertensive drug. It acts as an α1-adrenoceptor antagonist and as an 5-HT1A receptor agonist Although an initial report suggested that urapidil was also an α2-adrenoceptor agonist, this was not substantiated in later studies that demonstrated it was devoid of...
is an α1-adrenergic receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
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 blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s in the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
via central 5-HT1A activation increases heat
Heat
In physics and thermodynamics, heat is energy transferred from one body, region, or thermodynamic system to another due to thermal contact or thermal radiation when the systems are at different temperatures. It is often described as one of the fundamental processes of energy transfer between...
dissipation
Heat transfer
Heat transfer is a discipline of thermal engineering that concerns the exchange of thermal energy from one physical system to another. Heat transfer is classified into various mechanisms, such as heat conduction, convection, thermal radiation, and phase-change transfer...
from the organism out into the environment, causing a decrease in body temperature.
Activation of central 5-HT1A receptors triggers the release or inhibition of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
depending on species, presumably from the locus coeruleus, which then reduces or increases neuronal tone to the iris sphincter muscle
Iris sphincter muscle
The iris sphincter muscle is a muscle in the part of the eye called the iris...
by modulation of postsynaptic α2-adrenergic receptors within the Edinger-Westphal nucleus
Edinger-Westphal nucleus
The Edinger-Westphal nucleus is the accessory parasympathetic cranial nerve nucleus of the oculomotor nerve , supplying the constricting muscles of the iris...
, resulting in pupil dilation
Mydriasis
Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
in rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
s, and pupil constriction
Miosis
Miosis is the constriction of the pupil of the eye to two millimeters or less...
in primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s including human
Human
Humans are the only living species in the Homo genus...
s.
5-HT1A receptor agonists like buspirone
Buspirone
Buspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
and flesinoxan
Flesinoxan
Flesinoxan is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class. Originally developed as an antihypertensive agent, it was later found to possess antidepressant and anxiolytic effects in animals...
show efficacy in relieving anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, and buspirone
Buspirone
Buspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
and tandospirone
Tandospirone
Tandospirone , also known as metanopirone, is an anxiolytic and antidepressant used in China and Japan, where it is marketed by Dainippon Sumitomo Pharma...
are currently approved for these indications in various parts of the world. Others such as gepirone
Gepirone
Gepirone is a psychoactive drug and research chemical of the piperazine and azapirone chemical classes. It is currently under clinical development in an extended release form as an anxiolytic and antidepressant agent...
, flesinoxan
Flesinoxan
Flesinoxan is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class. Originally developed as an antihypertensive agent, it was later found to possess antidepressant and anxiolytic effects in animals...
, flibanserin
Flibanserin
Flibanserin is a drug that was investigated by Boehringer Ingelheim as a novel, non-hormonal treatment for pre-menopausal women with Hypoactive Sexual Desire Disorder . Development was terminated in October 2010 following a negative report by the U.S...
, and PRX-00023
PRX-00023
PRX-00023 is a drug of the phenylpiperazine class that was being developed by EPIX Pharmaceuticals Inc for the treatment of generalized anxiety disorder and major depressive disorder...
have also been investigated, though none have been fully developed and approved as of yet. Some of the atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s like aripiprazole
Aripiprazole
Aripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
are also partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
s at the 5-HT1A receptor and are sometimes used in low doses as augmentations to standard antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s like the selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s (SSRIs).
5-HT1A autoreceptor desensitization and increased 5-HT1A receptor postsynaptic activation via general increases in serotonin levels by serotonin precursor
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
supplementation
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
, serotonin reuptake inhibition, or monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
inhibition has been shown to be a major mediator in the therapeutic benefits of most mainstream antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
s and pharmaceuticals, including serotonin precursors like L-tryptophan and 5-HTP
5-Hydroxytryptophan
5-Hydroxytryptophan , also known as oxitriptan , is a naturally occurring amino acid and chemical precursor as well as metabolic intermediate in the biosynthesis of the neurotransmitters serotonin and melatonin from tryptophan....
, selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s (SSRIs), serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
Serotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
s (SNRIs), tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s (TCAs), tetracyclic antidepressant
Tetracyclic antidepressant
Tetracyclic antidepressants are a class of drugs used primarily as antidepressants that were first introduced in the 1970s. They are named after their chemical structure which contains four rings of atoms and are closely related to the tricyclic antidepressants which contain three rings of...
s (TeCAs), and monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s (MAOIs). 5-HT1A receptor activation likely plays a significant role in the positive effects of serotonin releasing agent
Releasing agent
A releasing agent , or simply releaser, is a drug that induces the release of a neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs use neurotransmitter release to exert their psychological and...
s (SRAs) like MDMA ("Ecstasy") as well.
5-HT1A receptors in the dorsal raphe nucleus are co-localized with neurokinin 1
Tachykinin receptor 1
The tachykinin receptor 1 also known as neurokinin 1 receptor or substance P receptor is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins...
(NK1) receptors and have been shown to inhibit the release of substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
, their endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
. In addition to being antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
and anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
in effect, 5-HT1A receptor activation has also been demonstrated to be antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
, 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
NK1 receptor antagonist
Neurokinin 1 antagonists are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. The discovery of neurokinin 1 receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.An example of...
are now in use for the treatment of nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and emesis, and are also being investigated for the treatment of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
.
5-HT1A receptor activation has been shown to increase dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
release in the medial prefrontal cortex, striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, and hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, and may be useful for improving the symptoms of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. 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 cognition
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
, learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
, and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
by inhibiting the release of glutamate and acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
in various areas of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. Conversely, 5-HT1A receptor antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
s such as lecozotan
Lecozotan
Lecozotan is an investigational drug by Wyeth tested for improvement of cognitive functions of Alzheimer's disease patients., the first Phase III clinical trial has been completed.- Method of action :...
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
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Other effects of 5-HT1A activation include decreased aggression
Aggression
In psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
or increased serenic behavior, increased sociability, decreased impulsivity
Impulsivity
Impulsivity is a personality trait characterized by the inclination of an individual to initiate behavior without adequate forethought as to the consequences of their actions, acting on the spur of the moment. Eysenck and Eysenck related impulsivity to risk-taking, lack of planning, and making up...
, inhibition of addictive
Behavioral addiction
Behavioral addiction is a form of addiction which does not rely on drugs or alcohol. Increasingly referred to as process addiction or non-substance-related addiction ) behavioral addiction includes a compulsion to repeatedly engage in an action until said action causes serious negative consequences...
behavior, facilitation of sexual behavior and arousal
Sexual arousal
Sexual arousal, or sexual excitement, is the arousal of sexual desire, during or in anticipation of sexual activity. Things that precipitate human sexual arousal are called erotic stimuli, or colloquially known as turn-ons. There are many potential stimuli, both physical or mental, which can cause...
, inhibition of penile erection, decreased food intake or anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, prolongation of REM sleep
Sleep
Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
latency, and enhanced breathing
Breathing
Breathing is the process that moves air in and out of the lungs. Aerobic organisms require oxygen to release energy via respiration, in the form of the metabolism of energy-rich molecules such as glucose. Breathing is only one process that delivers oxygen to where it is needed in the body and...
or hyperventilation
Hyperventilation
Hyperventilation or overbreathing is the state of breathing faster or deeper than normal, causing excessive expulsion of circulating carbon dioxide. It can result from a psychological state such as a panic attack, from a physiological condition such as metabolic acidosis, can be brought about by...
and reversal of opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
-induced respiratory depression.
Endocrinology
5-HT1A receptor activation induces the secretionSecretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
of various hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s including cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
, corticosterone
Corticosterone
Corticosterone is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands.-Roles:In many species, including amphibians, reptiles, rodents and birds, corticosterone is a main glucocorticoid, involved in regulation of fuel, immune reactions, and stress...
, adrenocorticotropic hormone
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH), oxytocin
Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
, prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
, growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
, and β-endorphin. The receptor does not affect vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
or renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
secretion, unlike the 5-HT2 receptor
5-HT2 receptor
The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT2 subfamily consists of three G protein-coupled receptors which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C...
s. It has been suggested that oxytocin release may contribute to the prosocial, antiaggressive or serenic, and anxiolytic properties observed upon activation of the receptor. β-Endorphin secretion likely contributes to antidepressant, anxiolytic, and analgesic effects.
Autoreceptors
5-HT1A receptors can be located on the cell body or somaSoma (biology)
The soma , or perikaryon , or cyton, is the bulbous end of a neuron, containing the cell nucleus. The word "soma" comes from the Greek σῶμα, meaning "body"; the soma of a neuron is often called the "cell body"...
, dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
s, axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s, and both presynaptically and postsynaptically in nerve terminals or synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s. Those located on the soma and dendrites are called somatodendritic, and those located presynaptically in the synapse are aptly titled presynaptic. As a group, they are known as autoreceptor
Autoreceptor
An autoreceptor is a receptor located on presynaptic nerve cell membranes and serves as a part of a feedback loop in signal transduction. It is sensitive only to those neurotransmitters or hormones that are released by the neuron in whose membrane the autoreceptor sits.Canonically, a presynaptic...
s. 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 moderate to high doses by directly stimulating the receptors in replacement of serotonin.
This autoreceptor-mediated inhibition of serotonin release has been postulated to be one of the reasons for the therapeutic lag that is commonly reported for most mainstream 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, serotonin reuptake inhibitors that also have 5-HT1A receptor antagonistic or partial agonistic properties such as vilazodone
Vilazodone
Vilazodone is an SSRI antidepressant developed by Clinical Data for the treatment of major depressive disorder. The chemical compound was originally developed by Merck KGaA ....
and SB-649,915
SB-649,915
SB-649,915 is a serotonin reuptake inhibitor and 5-HT1A and 5-HT1B receptor antagonist which is being investigated for its antidepressant effects. Relative to the selective serotonin reuptake inhibitors , SB-649,915 has a faster onset of action and may also have greater clinical efficacy as well...
are currently being investigated as novel antidepressants with a faster onset of action and greater efficacy than many of those currently available.
Unlike most drugs that elevate extracellular serotonin levels like the SSRIs and MAOIs, SRAs such as fenfluramine
Fenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...
and MDMA ("Ecstasy") fully bypass serotonin autoreceptors like 5-HT1A by forcing release to occur regardless of their inhibition. This is why SRAs display immediate and full effects in contrast to drugs like the SSRIs, which require several weeks of chronic dosing before therapeutic benefits are seen, and also why SRAs are much stronger than SSRIs and related compounds in effect, as they produce far more robust and balanced increases in extracellular serotonin concentrations. For these reasons, selective serotonin releasing agent
Selective serotonin releasing agent
A selective serotonin releasing agent is a type of drug which selectively induces the release of serotonin from the pre-synaptic neuron into the synapse...
s (SSRAs), including MDAI, MMAI, and 4-MTA, have been proposed as novel antidepressants with an immediate onset of action and far greater efficacy in comparison to most current treatments.
Sufficient doses of 5-HT1A receptor agonists themselves, like SRAs, are capable of fully bypassing the 5-HT1A autoreceptor-mediated inhibition of serotonin release, and therefore decreased 5-HT1A postsynaptic receptor activation as well, by directly agonizing the postsynaptic receptors in lieu of serotonin. It is important to note however, that unlike SRAs, 5-HT1A receptor agonists are incapable of bypassing the inhibitory effect of 5-HT1A autoreceptors located as heteroreceptor
Heteroreceptor
A heteroreceptor is a receptor regulating the synthesis and/or the release of mediators other than its own ligand.Heteroreceptors are presynaptic receptors that respond to neurotransmitters, neuromodulators, or neurohormones released from adjacent neurons or cells...
s in non-serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s where 5-HT1A postsynaptic receptors are not present, which instead of serotonin, modulate the release of other neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s such as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
or glutamate.
Ligands
The distribution of 5-HT1A receptors in the human brainHuman brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
may be imaged with the positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
using the radioligand
Radioligand
A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
[11C]WAY-100,635.
For example, one study has found increased 5-HT1A binding in type 2 diabetes. Another PET study found a negative correlation between the amount of 5-HT1A binding in the raphe nuclei
Raphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...
, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and neocortex
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
and a self-reported tendency to have spiritual experiences. Labeled with tritium
Tritium
Tritium is a radioactive isotope of hydrogen. The nucleus of tritium contains one proton and two neutrons, whereas the nucleus of protium contains one proton and no neutrons...
, WAY-100,635 may also be used in autoradiography.
Agonists
Antagonists
Genetics
The 5-HT1A receptor is coded by the HTR1A geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. There are several human polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
s associated with this gene. A 2007 review listed 27 single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
s (SNP). The most investigated SNPs are C-1019G (rs6295
Rs6295
rs6295, also called CG, is a gene variation—a single nucleotide polymorphism —in the HTR1A gene. It is one of the most investigated SNPs of its gene...
), C-1018G, Ile28Val (rs1799921), Arg219Leu (rs1800044), and Gly22Ser (rs1799920). Some of the other SNPs are Pro16Leu, Gly272Asp, and the synonymous polymorphism G294A (rs6294
Rs6294
Rs6294, also called G294A, is a gene variation—a single nucleotide polymorphism — in the HTR1A gene.CG is another SNP in the HTR1A gene....
). These gene variants have been studied in relation to psychiatric disorders with no definitive results.
Interactions
The 5-HT1A receptor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with brain-derived neurotrophic factor
Brain-derived neurotrophic factor
Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
(BDNF), which may play a major role in its regulation of mood and anxiety. It has also been shown to interact with sphingosine-1-phosphate receptor 1 (S1PR1).