Molecular pharmacology and biology of 5-HT1C receptors

doi:10.1016/0165-6147(88)90174-5

Trends in Pharmacological Sciences

Volume 9, Issue 3, March 1988, Pages 89-94

https://doi.org/10.1016/0165-6147(88)90174-5 Get rights and content

Abstract

The pharmacology of 5-HT_1C receptors, which are found mainly in the choroid plexus of various species, is very close to that of 5-HT₂ receptors. They display similar affinities to a variety of drugs and both are coupled through G proteins to phospholipase C activation. Daniel Hoyer reports on the recent progress made on the molecular biology of 5-HT_1C receptors, which have been expressed in Xenopus laevis oocytes and cloned via a functional assay. Partial sequence deduced from the cDNA suggests that this 5-HT receptor has structural similarities with other receptors coupled to G proteins. These aspects and evidence that 5-HT_1C receptors may indeed be different from 5-HT₂ receptors will be reviewed in this short article.

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Distribution of 5-HT receptors in the central nervous system: an update
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Citation Excerpt :
Since this receptor was also labeled by [3H]-5-HT, but not [3H]-spiperone, they were initially identified as being similar to other 5-HT1 receptors and thus called 5-HT1C (Hoyer et al.1985b; Pazos et al., 1987, 1984; Pazos & Palacios, 1985); see Palacios et al. (2017) for a historical overview. When the receptor was cloned several years later, the 5-HT1C was recognized to belong structurally to the 5-HT2 class (Hoyer, 1988) and was thus renamed 5-HT2C (Hoyer et al., 1994; Humphrey et al., 1993). Incidentally, the 5-HT2A receptor was cloned by homology to 5-HT2C (Pritchett et al., 1988).
Almost 10 years have passed since we wrote the review on the “Distribution of 5-HT receptors in the central nervous system” in this series (Mengod, Cortés, Vilaró, & Hoyer, 2010). The number of 5-HT receptors remains the same: 14 receptor subtypes grouped in seven families. New findings are related to the identification of the phenotype of the cells expressing 5-HT receptors and their colocalization with other related neurotransmitters and neurotransmitter receptors, some in neurons, others in glial cells or astrocytes (Zhang et al., 2010). The application of immunohistochemistry adds new information about this colocalization. A number of studies are centered on the expression of 5-HT receptors in brain areas related with migraine. New labeled ligands have been developed and preferentially used for positron emission tomography studies in various pathological conditions, as such molecules are considered as potential treatments and/or biomarkers for various diseases.
Serotonin receptors nomenclature
2019, The Serotonin System: History, Neuropharmacology, and Pathology
Serotonin (5-hydroxytryptamine, 5-HT) acts on two superfamilies of receptors. 5-HT receptors are currently divided into seven classes (5-HT₁ to 5-HT₇), based on structural, transductional, and operational features. The effects of 5-HT are mediated by at least 14 distinct G protein-coupled receptors (GPCRs) of the type A family and one or more ligand-gated ion channels (5-HT₃) of the Cys-loop family, which may form homo or heteropentamers, similarly to nicotinic receptors. This degree of structural diversity is not unique (glutamate receptors represent another such example of complexity), but clearly underscores the physiological and pathophysiological importance of 5-HT. An even greater degree of operational diversity is supported by the existence of a great number of splice and editing variants for several 5-HT receptors and their possible modulation by accessory proteins and chaperones. The potential to form homo- or heteromers for both GPCRs and ligand-gated channels is highly probable (even with receptors for other neurotransmitters), although this is beyond the scope of this short chapter.
Atorvastatin evokes a serotonergic system-dependent antidepressant-like effect in mice
2014, Pharmacology Biochemistry and Behavior
Citation Excerpt :
It can be highlighted by studies that showed a reduced cerebrospinal fluid concentration of 5-HT and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA) in postmortem brain tissue of depressed or suicidal patients (Asberg et al., 1976; Roy et al., 1989). 5-HT can interact with multiple receptors, and to date seven families have been characterized (5HT1R–5HT7R), and with exception to 5HT3R that is a ligand-gated ion channel, they are all G-protein-coupled receptors (Barnes and Sharp, 1999; Hoyer, 1988; Kriegebaum et al., 2010). The 5-HT1A receptor subtype is the best studied (Glennon and Dukat, 1991; Pessoa-Mahana et al., 2003), and it is generally accepted to be involved in psychiatric disorders such as anxiety and depression (Blier and Abbott, 2001).
Atorvastatin is a statin largely used in the treatment of hypercholesterolemia and recently revealed as a neuroprotective agent. The antidepressant-like effect of acute atorvastatin treatment in mice has been previously demonstrated by our laboratory. The purpose of this study was to explore the contribution of the serotonergic system in the antidepressant-like effect of atorvastatin in mice. Data demonstrate that the serotonin (5-HT) depleting agent p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p.) completely abolished atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. Besides atorvastatin, fluoxetine (10 mg/kg, p.o.), a serotonin selective reuptake inhibitor (SSRI) was able to exert an antidepressant-like effect, but any of them changed 5-HT content in the hippocampus or frontal cortex. The 5H-T1A (WAY100635, 0.1 mg/kg, s.c) or the 5-HT2A/2C (ketanserin, 5 mg/kg, s.c.) receptor antagonists prevented atorvastatin antidepressant-like effect. In addition, a combinatory antidepressant-like effect was observed when mice received the co-administration of sub-effective doses of atorvastatin (0.01 mg/kg, p.o.) and the SSRI fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.). Taken together, these results indicate that the antidepressant-like effect of atorvastatin depends on the serotonergic system modulation.
The effect of the 5-HT<inf>2A/2C</inf> receptor agonist DOI on micturition in rats with chronic spinal cord injury
2013, Journal of Urology
We examined the effects of the 5-HT_2A/2C receptor agonist DOI on micturition in chronic spinal cord injured rats.
Female Sprague-Dawley® rats were used. Spinal cord injury was produced by transection at the T10 level. A cystometric study was performed 8 to 12 weeks after transection. Cystometrograms were done using urethane anesthesia in all rats. The selective 5-HT_2A antagonist ketanserin was administered after each DOI dose-response curve. All drugs were administered intravenously.
Compared to controls, spinal cord injured rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. In spinal cord injured rats DOI (0.01 to 0.3 mg/kg) induced significant dose dependent increases in micturition volume and decreases in residual volume, resulting in increased voiding efficiency. Cystometrogram measurements showed a dose dependent increase in high frequency oscillation activity, evident as an increased number of small oscillation per voiding. This correlated with the improved voiding efficiency. Ketanserin (0.1 mg/kg) partially or completely reversed the DOI induced changes.
High frequency oscillation seems to reflect external urethral sphincter burst activity during voiding. Bladder voiding efficiency and high frequency oscillation activity were decreased in spinal cord injured rats. High frequency oscillation activity can be enhanced by 5-HT_2A receptor agonism, improving voiding efficiency. To our knowledge it remains to be studied whether these results may have implications for the future treatment of voiding dysfunction in patients with spinal cord injury.
Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens
2011, Neuropharmacology
Citation Excerpt :
This hypothesis was proposed prior to the discovery of 5-HT2C sites, and was partially based on evidence demonstrating that ketanserin and pirenperone block the behavioral effects of hallucinogens in several animal paradigms. However, ketanserin and pirenperone exhibit less than a 100-fold difference in affinity for 5-HT2A receptors versus 5-HT2C receptors, and therefore display only moderate selectivity for the 5-HT2A receptor (Newton et al., 1996; Hoyer, 1988a,b). It was also reported that there is a significant correlation (r = 0.78) between the affinities of various phenylalkylamine hallucinogens for 5-HT2C receptors and their psychoactive potency in humans (Titeler et al., 1988).
Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT₂ receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT_2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT₂ and non-5-HT₂ receptors.
Molecular biology of 5-HT receptors
2008, Behavioural Brain Research
Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter whose effects are mediated by at least 13 distinct G protein-coupled receptors (GPCRs) of the type A family which includes the monoamine receptors and a combination of ligand-gated ion channels (5-HT₃) of the Cys loop family which constitutes heteropentamers. 5-HT receptors are currently divided into seven classes (5-HT₁ to 5-HT₇), based on structural, transductional and operational features. While this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity is supported by the existence of a great number of splice and editing variants for several 5-HT receptors, their possible modulation by accessory proteins and chaperones, as well as their potential to form homo or heteromers both at the GPCR and at the ligand-gated channel level.

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Tips reviewsMolecular pharmacology and biology of 5-HT1C receptors

Abstract

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Phamacol.

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Brain Res.

Neurosci. Lett.

Brain Res.

Brain Res.

New-science

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Mol. Brain Res.

Mol. Brain Res.

Mol. Brain Res.

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Molecular pharmacology and biology of 5-HT_1C receptors