|5-hydroxytryptamine (serotonin) receptor 1A, G protein-coupled|
|RNA expression pattern|
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.
The 5-HT1A receptor is the most widespread of all the 5-HT receptors. In the central nervous system, 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 autoreceptors, whereas those in other areas such as the hippocampus are postsynaptic receptors.
5-HT1A receptor agonists are involved in neuromodulation. They 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 vessels 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 rodents, and pupil constriction in primates including humans.
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 naluzotan have also been investigated, though none have been fully developed and approved yet. Some of the atypical antipsychotics like aripiprazole are also partial agonists at the 5-HT1A receptor and are sometimes used in low doses as augmentations to standard antidepressants like the 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 monoamine oxidase inhibition has been shown to be a major mediator in the therapeutic benefits of most mainstream antidepressant supplements and pharmaceuticals, including serotonin precursors like L-tryptophan and 5-HTP, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), and monoamine oxidase inhibitors (MAOIs). 5-HT1A receptor activation likely plays a significant role in the positive effects of serotonin releasing agents (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 memory (affecting declarative and non-declarative memory functions) and learning (due to interference with memory-encoding mechanisms), by inhibiting the release of glutamate and acetylcholine in various areas of the brain. Conversely, 5-HT1A receptor antagonists 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 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 latency
- Reversal of opioid-induced respiratory depression.
5-HT1A receptor activation induces the secretion of various hormones 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 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 likely contributes to antidepressant, anxiolytic, and analgesic effects.
5-HT1A receptors can be located on the cell body or soma, dendrites, axons, and both presynaptically and postsynaptically in nerve terminals or synapses. Those located on the soma and dendrites are called somatodendritic, and those located presynaptically in the synapse are aptly titled presynaptic. As a group, those receptors that are sensitive to the transmitter 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 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 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 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 agents (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, like SRAs, are capable of fully bypassing the 5-HT1A autoreceptor-mediated inhibition of serotonin release, and therefore increase 5-HT1A postsynaptic receptor activation, by directly agonizing the postsynaptic receptors in lieu of serotonin. It is important to note that unlike SRAs, 5-HT1A receptor agonists are incapable of bypassing the inhibitory effect of 5-HT1A autoreceptors located as heteroreceptors in non-serotonergic synapses where 5-HT1A postsynaptic receptors are not present, which instead of serotonin, modulate the release of other neurotransmitters such as dopamine or glutamate.
The distribution of 5-HT1A receptors in the human brain 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.
Partial Agonists/Unknown Efficacy Agonists
- Bay R 1531
- Ginkgo Biloba
- Lysergide (LSD)
- Osemozotan (partial at postsynaptic receptors)
The 5-HT1A receptor is coded by the HTR1A gene. 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.