Serotonin, serotonin receptors, serotonin receptor subtype agonists and pain.
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Analgesics↗
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The tantalizing triplet of pulmonary hypertension-BMP receptors, serotonin receptors, and angiopoietins.
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Angiopoietins↗
Characterization of the Caenorhabditis elegans G protein-coupled serotonin receptors.
Serotonin (5-HT) regulates a wide range of behaviors in Caenorhabditis elegans, including egg laying, male mating, locomotion and pharyngeal pumping. So far, four serotonin receptors have been described in the nematode C. elegans, three of which are G protein-coupled receptors (GPCR), (SER-1, SER-4 and SER-7), and one is an ion channel (MOD-1). By searching the C. elegans genome for additional 5-HT GPCR genes, we identified five further genes which encode putative 5-HT receptors, based on sequence similarities to 5-HT receptors from other species. Using loss-of-function mutants and RNAi, we performed a systematic study of the role of the eight GPCR genes in serotonin-modulated behaviors of C. elegans (F59C12.2, Y22D7AR.13, K02F2.6, C09B7.1, M03F4.3, F16D3.7, T02E9.3, C24A8.1). We also examined their expression patterns. Finally, we tested whether the most likely candidate receptors were able to modulate adenylate cyclase activity in transfected cells in a 5-HT-dependent manner. This paper is the first comprehensive study of G protein-coupled serotonin receptors of C. elegans. It provides a direct comparison of the expression patterns and functional roles for 5-HT receptors in C. elegans.
Amino Acid Sequence↗
New 3-[4-(3-substituted phenyl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants.
In this paper a series of new 3-[4-(3-substituted phenyl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propanol derivatives is presented as a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. The 5-HT1A receptor and 5-HT transporter binding affinities of hydroxylic compounds 4 a-e have been determined. The new compounds present nanomolar affinity for both activities, and 1-(benzo[b]thiophen-3-yl)-3-[4-(3-methoxyphenyl)piperazin-1-yl]propan-1-ol (4d) shows values (nM) of Ki = 86 for 5-HT1A receptors and Ki = 76 for the serotonin transporter, respectively.
Antidepressive Agents, Second-Generation↗
New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants.
A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (8) show values (nM) of K(i)=30 and 2.3 for 5-HT1A receptors and K(i)=30 and 12 for serotonin transporters, respectively. In GTPgammaS binding assays, compound 8 revealed antagonist properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.
Animals↗
Inefficient cell-surface expression of hybrid complexes formed by the co-assembly of neuronal nicotinic acetylcholine receptor and serotonin receptor subunits.
Previous studies have demonstrated that relatively low levels of alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs) are expressed on the cell surface of transfected mammalian cell lines but that surface expression levels can be dramatically up-regulated by co-expression of these subunits with chimeric subunits containing the N-terminal portion of the neuronal nAChR alpha4 or beta2 subunits together with the C-terminal domain of the 5-HT(3A) subunit. Recent work has also suggested that the nAChR alpha4 subunit can co-assemble in a "promiscuous" manner with the serotonin receptor 5-HT(3A) subunit to form functional hybrid receptors. In this study we have examined whether co-assembly of either alpha4 or beta2 with 5-HT(3A) itself (rather than with the alpha4/5-HT(3A) or beta2/5-HT(3A) subunit chimeras) can also facilitate cell surface expression of alpha4 and beta2 subunits in transfected mammalian cells. Evidence has been obtained by immunoprecipitation, cell-surface antibody binding and radioligand binding which indicates that the 5-HT(3A) can co-assemble with both the alpha4 and beta2 nAChR subunits. We conclude, however, that co-assembly of 5-HT(3A) with either alpha4 or beta2 does not result in efficient cell surface expression of the nAChR subunits and that co-assembled hybrid (nAChR subunit + 5-HT(3)R subunit) receptor complexes are largely retained within the cell.
Cell Line↗
Structure and variation of three canine genes involved in serotonin binding and transport: the serotonin receptor 1A gene (htr1A), serotonin receptor 2A gene (htr2A), and serotonin transporter gene (slc6A4).
Aggressive behavior is the most frequently encountered behavioral problem in dogs. Abnormalities in brain serotonin metabolism have been described in aggressive dogs. We studied canine serotonergic genes to investigate genetic factors underlying canine aggression. Here, we describe the characterization of three genes of the canine serotonergic system: the serotonin receptor 1A and 2A gene (htr1A and htr2A) and the serotonin transporter gene (slc6A4). We isolated canine bacterial artificial chromosome clones containing these genes and designed oligonucleotides for genomic sequencing of coding regions and intron-exon boundaries. Golden retrievers were analyzed for DNA sequence variations. We found two nonsynonymous single nucleotide polymorphisms (SNPs) in the coding sequence of htr1A; one SNP close to a splice site in htr2A; and two SNPs in slc6A4, one in the coding sequence and one close to a splice site. In addition, we identified a polymorphic microsatellite marker for each gene. Htr1A is a strong candidate for involvement in the domestication of the dog. We genotyped the htr1A SNPs in 41 dogs of seven breeds with diverse behavioral characteristics. At least three SNP haplotypes were found. Our results do not support involvement of the gene in domestication.
Amino Acid Sequence↗
Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.
Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.
Amino Acid Sequence↗
New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-2-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants.
Some benzo[b]thiophene derivatives with different substituents in positions 3 and 5 have been synthesized in order to obtain new dual antidepressant drugs. Compounds derived from 2-acetyl-3-methylbenzo[b]thiophene or 2-acetyl-3,5-dimethylbenzo[b]thiophene were prepared with two different phenylpiperazines (2-methoxy and 2-hydroxyphenylpiperazine) and evaluated for in vitro 5-HT1A receptor affinity and serotonin reuptake inhibition by radioligand assays. Compound 1-(3,5-dimethylbenzo[b]thiophen-2-yl)-3-[4-(2-methoxyphenyl)piperazin-1- yl]propan-1-ol (II.2.a) shows good values (nM) for both activities: Ki = 85 for 5-HT1A receptor and Ki = 120 for serotonin transporter.
Antidepressive Agents↗
Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims.
Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT(1A) receptors in localized regions of the prefrontal cortex. In depression, there is a diffuse decrease in SERT binding throughout the dorsoventral extent of the prefrontal cortex. Serotonergic innervation of the prefrontal cortex arises predominantly from neurons in the brainstem dorsal raphe nucleus (DRN). We, therefore, examined postmortem SERT binding and mRNA expression, as well as 5-HT(1A) autoreceptor binding in the DRN of 10 matched pairs of controls and depressed suicide victims. The concentration of SERT sites, SERT mRNA, and 5-HT(1A) binding was not different between controls and suicides (p >.05). In the DRN of suicides, the volume of tissue defined by 5-HT(1A) binding was 40% smaller than controls. An index of the total number of 5-HT(1A) receptors (receptor binding x volume of receptor distribution) was 43.3% lower in the DRN of suicides, compared with controls. The suicide group had 54% fewer DRN neurons expressing SERT mRNA compared with controls. In the serotonin neurons that expressed the SERT gene, expression per neuron was greater in suicides. Less total 5-HT(1A) and SERT binding is consistent with results of in vivo studies in depression. Less feedback inhibition of serotonin DRN firing via 5-HT(1A) autoreceptors and enhancement of serotonin action due to less uptake of serotonin, is consistent with compensatory changes in response to hypofunction in depressed suicides.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
New 3-[4-(2,3-dihydro-14-benzodioxin-5-yl)piperazin-1-yl]-1-(5-substituted benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT(1A) serotonin receptors and serotonin transporter as a new class of antidepressants.
Compounds derived from 2,3-dihydro-(1,4-benzodioxin-5-yl)piperazine and benzo[b]thiophene with different substituents in 5 position (H, F, NO2, NH2, CH3 and OH) have been synthesized in order to obtain new dual antidepressant drugs. The final compounds were evaluated for in vitro 5-HT(1A) receptor affinity and serotonin reuptake inhibition by radioligand assays. Compounds 1-(5-nitrobenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propan-1-ol (4c) (Ki = 6.8 for 5-HT(1A) receptor and Ki = 14 for 5-HT transporter) and 1-(5-hydroxybenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl] propan-1-ol (4f) (Ki = 6.2 for 5-HT(1A) receptor and Ki = 18.2 for 5-HT transporter) showed the best results for both activities.
Animals↗
New 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives, with dual action at 5-HT1A serotonin receptors and serotonin transporter, as a new class of antidepressants.
In a search toward new and efficient antidepressants, 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor antagonism. This dual pharmacological profile should lead, in principle, to a rapid and pronounced enhancement in serotoninergic neurotransmission and consequently to a more efficacious treatment of depression. The design was based on coupling structural moieties related to inhibition of serotonin reuptake, such as gamma-phenoxypropylamines, to arylpiperazines, typical 5-HT1A ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and 5-HT1A receptors. Antidepressant-like activity was initially assayed in the forced swimming test with those compounds with Ki < 200 nM in both binding studies. Functional characterization was performed by measuring the intrinsic effect on rectal temperature in mice and also the antagonism to 8-OH-DPAT-induced hypothermia. The most efficacious compounds (12f, 23gE, 28a, and 28b) were further explored for their ability to antagonize 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP formation in a cell line expressing the 5-HT1A receptor. Furthermore, the antidepressant-like properties of 12f, 28a, and 28b, which exhibited 5-HT1A receptor antagonistic property in the latter study, were also evaluated in the learned helplessness test in rats. Among these three compounds, 28b (1-benzo[b]thiophene-3-yl)-3-[4-(2-methoxyphenyl)-1-ylpropan-1-ol) showed the higher affinity at both the 5-HT transporter and 5-HT1A receptors (Ki = 20 nM in both cases) and was also active in the other pharmacological tests. Such a pharmacological profile could lead to a new class of antidepressants with a dual mechanism of action and a faster onset of action.
Animals↗
A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders.
The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR=1.14, CI: 1.03-1.26, P=0.015 for the promoter locus (N=3467) and Mantel-Haenszel Weighted odds ratio OR=1.18, CI: 1.05-1.32, P=0.004 for the VNTR locus (N=3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT.
Carrier Proteins↗
How do antidepressants affect serotonin receptors? The role of serotonin receptors in the therapeutic and side effect profile of the SSRIs.
The serotonin selective reuptake inhibitors (SSRIs) have proved to be an important development in the treatment of depression because of both their greater practical ease of use and their selective primary action on a single binding site. Their efficacy in depressive illness of a range of severities, but also in obsessive-compulsive disorder and panic, is largely established. The onset of action of the SSRIs may be delayed by autoinhibition at the cell bodies of raphe neurons. This suggests that blockade of autoreceptors may speed the onset of antidepressant action by SSRIs. The main unwanted effects of the SSRIs occur in relation to gastrointestinal, sleep, and orgasmic disturbances. However, the total side effect burden is less than that associated with the older, less selective compounds, and there are clear hypotheses for how the side effects that do occur may be mediated and hence how they may be reduced by either adjunctive treatment or design of new compounds.
Autoreceptors↗
Hyper- and hyposensitivity of central serotonin receptors:[3H]serotonin binding and functional studies in the rat.
The effect of repeated treatment with D-fenfluramine, a serotonin releaser, or methergoline, a serotonin antagonist, on [3H]5-HT binding was studied in various rat brain areas. In animals with the same pretreatments, the anorectic activity of m-chlorophenylpiperazine, a serotonin agonist, was investigated. A 14-day treatment with D-fenfluramine caused a significant decrease in the number of [3H]5-HT binding sites (Bmax) in the diencephalon. A reduction of binding sites was found in the cortex too when D-fenfluramine was administered for 28 days. Methergoline caused no changes of [3H)5-HT binding in any brain area examined when given for 14 days but 28-day treatment led to a significant increase in the striatum, hippocampus and cortex. D-Fenfluramine and methergoline caused, respectively, a decrease and increase in the effect of m-chlorophenylpiperazine on food intake. The data show that central 5-HT receptor numbers and sensitivity may change after repeated treatments with drugs acting on brain serotonin.
Animals↗
Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter.
Definitive conclusions on the role of serotonin receptors and transporter in suicide and depression have been elusive in studies of postmortem brain tissue. A number of methodological differences in these studies have made it difficult to reach a consensus, but crucial issues are being identified and incorporated into newer studies. This review will follow the evolution of serotonin receptor and transporter studies in postmortem tissues that initially focused on suicide and gradually incorporated depressive disorders as psychiatric assessments were increasingly performed. Studies in postmortem tissues on the serotonin-1A and serotonin-2A receptors and the serotonin transporter will be reviewed and compared with imaging studies of the same sites in depressed subjects. Critical issues to control in future studies of serotonin receptors in postmortem tissues include variables such as the cause of death (i.e. suicide), the specific psychiatric diagnoses of the subjects, whether the disorder was in remission at the time of death, long-term medication histories, psychoactive substance use disorders, the smoking history, the hemisphere from which tissues were dissected, and the specific cytoarchitectonic region to be evaluated. Carefully controlled studies in postmortem tissues will ensure a greater likelihood of reaching a consensus on the involvement of monoamine measures in the etiology of depression.
Autopsy↗
Constitutive activity of G-protein coupled receptors: emphasis on serotonin receptors.
Several lines of evidence indicate that G-protein coupled receptors (GPCR) may exist in a state that allows a tonic level of stimulation in vivo (constitutive activity). Several native forms of GPCR, when expressed in recombinant cell lines, display significant signal transduction stimulation in the absence of activating ligand. Many GPCR, including three serotonin receptors, display robust constitutive activation upon the mutation of a single amino acid, indicating mutations producing inappropriate constitutive activation may be etiological factors in diseases. If constitutive activity of GPCR is as common a phenomenon as some researchers suspect, this would suggest significant alterations in the classical model of ligand-receptor interactions. One of the most significant implications of constitutive activity for pharmacologists and medicinal chemists, is the possibility of developing drugs that lower the level of constitutive activity. Such compounds have been termed inverse agonists . These drugs, in theory, would have different physiological effects, and therefore possibly different therapeutic potential, than classical competitive receptor antagonists ( neutral antagonists ). Theoretical issues concerning constitutive activity in the GPCR family and some of the evidence supporting the existence of constitutive activity in the GPCR family is reviewed. Studies are presented demonstrating the procedures for producing and characterizing constitutive activated forms of serotonin receptors, including the demonstration of inverse agonist activity of drugs on these receptors.
Animals↗
Postnatal changes in serotonin receptors following prenatal alterations in serotonin levels: further evidence for functional fetal serotonin receptors.
Recent work by ourselves and others has indicated that serotonin (5-HT) acts as a regulator of neuronal growth in fetal tissue, probably through an action on the high affinity 5-HT receptors known to be present. In order for our hypothesis to be correct, these receptors must be shown to be functional in fetal tissue. Furthermore, since 5-HT has a dual role in neuronal development, these receptors must be functional both in the region of the serotonergic cell body (brainstem) and in projection areas (forebrain). We have tested the functional status of fetal 5-HT receptors by testing their ability to adapt to changes in the level of 5-HT. Pregnant rats were treated with saline, p-chlorophenylalanine (a 5-HT depletor) or 5-methoxytryptamine (a 5-HT agonist) and the characteristics of the high affinity 5-HT receptors in the rat pups determined using a binding assay with [3H]5-HT. Our results show that both forebrain and brainstem receptors respond to alterations in transmitter level in a manner similar to adult brain. Thus, fetal 5-HT receptors are functional and capable of playing a role in neuronal development.
5-Methoxytryptamine↗