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.
Distribution[edit | edit source]
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 nucelus 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.
Function[edit | edit source]
Neuromodulation[edit | edit source]
5-HT1A receptor agonists decrease blood pressure and heart rate or cause hypotension 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 or hypothermia.
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 or mydriasis in rodents, and pupil constriction or miosis in primates like 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 PRX-00023 have also been investigated, though none have been fully developed and approved as of yet. Some of the atypical antipsychotics like aripiprazole are also partial agonists at the 5-HT1A receptor and are often 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 cognition, learning, and memory 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 include decreased aggression or increased serenic behavior, increased sociability, increased 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.
Endocrinology[edit | edit source]
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 or serenic, and anxiolytic properties observed upon activation of the receptor. β-Endorphin secretion likely contributes to antidepressant, anxiolytic, and analgesic effects.
Autoreceptors[edit | edit source]
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, they are known as autoreceptors. 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 properties such as SB-649915 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 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 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 mentionable, however, 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.
Ligands[edit | edit source]
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.
Agonists[edit | edit source]
- Lu AA21004
Antagonists[edit | edit source]
Genetics[edit | edit source]
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.
Interactions[edit | edit source]
The 5-HT1A 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. It has also been shown to interact with sphingosine-1-phosphate receptor 1 (S1PR1).
See also[edit | edit source]
References[edit | edit source]
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Further reading[edit | edit source]
- el Mestikawy S, Fargin A, Raymond JR, et al. (1991). The 5-HT1A receptor: an overview of recent advances. Neurochem. Res. 16 (1): 1–10.
- Hensler JG (2003). Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration. Life Sci. 72 (15): 1665–82.
- Van Oekelen D, Luyten WH, Leysen JE (2003). 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci. 72 (22): 2429–49.
- Lesch KP, Gutknecht L (2005). Focus on The 5-HT1A receptor: emerging role of a gene regulatory variant in psychopathology and pharmacogenetics. Int. J. Neuropsychopharmacol. 7 (4): 381–5.
- Kalipatnapu S, Chattopadhyay A (2006). Membrane protein solubilization: recent advances and challenges in solubilization of serotonin1A receptors. IUBMB Life 57 (7): 505–12.
- Varrault A, Bockaert J, Waeber C (1992). Activation of 5-HT1A receptors expressed in NIH-3T3 cells induces focus formation and potentiates EGF effect on DNA synthesis. Mol. Biol. Cell 3 (9): 961–9.
- Levy FO, Gudermann T, Perez-Reyes E, et al. (1992). Molecular cloning of a human serotonin receptor (S12) with a pharmacological profile resembling that of the 5-HT1D subtype. J. Biol. Chem. 267 (11): 7553–62.
- Melmer G, Sherrington R, Mankoo B, et al. (1992). A cosmid clone for the 5HT1A receptor (HTR1A) reveals a TaqI RFLP that shows tight linkage to dna loci D5S6, D5S39, and D5S76. Genomics 11 (3): 767–9.
- Parks CL, Chang LS, Shenk T (1992). A polymerase chain reaction mediated by a single primer: cloning of genomic sequences adjacent to a serotonin receptor protein coding region. Nucleic Acids Res. 19 (25): 7155–60.
- Gilliam TC, Freimer NB, Kaufmann CA, et al. (1990). Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia. Genomics 5 (4): 940–4.
- Kobilka BK, Frielle T, Collins S, et al. (1987). An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins. Nature 329 (6134): 75–9.
- Fargin A, Raymond JR, Lohse MJ, et al. (1988). The genomic clone G-21, which resembles a beta-adrenergic receptor sequence encodes the 5-HT1A receptor. Nature 335 (6188): 358–60.
- Nakhai B, Nielsen DA, Linnoila M, Goldman D (1995). Two naturally occurring amino acid substitutions in the human 5-HT1A receptor: glycine 22 to serine 22 and isoleucine 28 to valine 28. Biochem. Biophys. Res. Commun. 210 (2): 530–6.
- Aune TM, McGrath KM, Sarr T, et al. (1993). Expression of 5HT1a receptors on activated human T cells. Regulation of cyclic AMP levels and T cell proliferation by 5-hydroxytryptamine. J. Immunol. 151 (3): 1175–83.
- Parks CL, Shenk T (1996). The serotonin 1a receptor gene contains a TATA-less promoter that responds to MAZ and Sp1. J. Biol. Chem. 271 (8): 4417–30.
- Stockmeier CA, Shapiro LA, Dilley GE, et al. (1998). Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J. Neurosci. 18 (18): 7394–401.
- Kawanishi Y, Harada S, Tachikawa H, et al. (1998). Novel mutations in the promoter and coding region of the human 5-HT1A receptor gene and association analysis in schizophrenia. Am. J. Med. Genet. 81 (5): 434–9.
- Salim K, Fenton T, Bacha J, et al. (2002). Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation. J. Biol. Chem. 277 (18): 15482–5.
[edit | edit source]
- 5-HT1A. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Cell physiology: cell signaling
|Types of proteins|