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5-HT2A: a serotonin receptor with a possible role in joint diseases
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Serotonin (5-HT), an amino acid derivative and neurotransmitter, has for long been studied in relation to inflammation. It is an endogenous ligand for several different types of serotonin receptors. The serotonin receptor 5-HT2A has been reported to have a role in the pathophysiology of arthritis in animal experiment models. However, no studies into this subject have been reported in man.

Objective

The objectives of this project were firstly, to examine possible associations for the 5-HT2A receptor and also for the gene (HTR2A) encoding for the receptor with arthritis in man and secondly, to explore possible mechanisms underlying such associations.

Methods

The density and affinity of platelet 5-HT2A receptors were determined in 43 patients with a common inflammatory joint disease, i. e., rheumatoid arthritis (RA), in comparison with matched controls using a radio-ligand assay. The effects of treatment with prednisolone on 5-HT2A density and affinity were also examined in 27 individuals diagnosed with polymyalgia rheumatica before and after start of treatment. In addition, possible candidate HTR2A genes were studied in relation to RA in two Swedish cohorts incorporating a total of 2450 RA patients. Furthermore, a register study using reports of joint symptoms as adverse drug reactions (ADRs) in the Swedish and the WHO ADR databases was undertaken. The proportion of reports concerning joint symptoms in relation to all ADR reports and to sales figures was analysed for 5-HT2A blocking atypical antidepressant substances compared with another group of antidepressants, i. e., selective serotonin re-uptake inhibitors (SSRIs), used for similar clinical indications.

Results

The mean density of 5-HT2A receptors in RA patients was significantly lower than in controls, 45.3 versus 57.4 fmol/mg protein (p = 0.004). There was no significant difference in affinity. Variation of four single nucleotide polymorphisms (SNPs) (rs6314, rs1328674, rs6313 and rs6311) in the HTR2A gene was associated with RA, although not significantly so for all SNPs after testing for multiple comparisons. The proportion of joint symptoms reported as ADRs, relative to all ADRs was significantly higher for the 5-HT2A blocking antidepressants compared with the SSRIs in both databases (p< 0.001). In the Swedish material the comparison of ADRs was also related to sales figures, showing a considerable higher frequency of joint symptoms for the 5-HT2A antagonists (p< 0.001). The density of 5-HT2A receptors increased after treatment with prednisolone in 23 out of 27 individuals. The mean density at baseline was 45.2 versus 64.9 fmol/mg protein at the end of the study (p=0.001). There were no significant differences in affinity during the treatment period, although a low affinity at baseline was a predictor for higher density following treatment with prednisolone.

Conclusions

The density of 5-HT2A receptors, reflecting the number of receptors, was markedly reduced in a cohort of patients with RA from Northern Sweden. This may depend, at least in part, on an association between RA and certain HTR2A SNPs. Genetically determined or acquired low levels of accessible 5-HT2A receptors may contribute to susceptibility for development of joint symptoms, not only in RA but more generally, e. g., joint ADRs caused by 5-HT2A blocking atypical antidepressants. The benefits of treatment with glucocorticoids may, at least partially, be mediated by an effect on 5-HT2A receptors.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 79 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1547
Keyword [en]
5-HT2A serotonin receptor, serotonin, rheumatoid arthritis, adverse drug reaction, HTR2A, glucocorticoids
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
Identifiers
URN: urn:nbn:se:umu:diva-64013ISBN: 978-91-7459-549-9 (print)OAI: oai:DiVA.org:umu-64013DiVA: diva2:586490
Public defence
2013-01-28, Vårdvetarhusets aula, Vårdvetarhuset, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-01-14 Created: 2013-01-11 Last updated: 2013-01-14Bibliographically approved
List of papers
1. Decreased density of serotonin 5-HT2A receptors in rheumatoid arthritis
Open this publication in new window or tab >>Decreased density of serotonin 5-HT2A receptors in rheumatoid arthritis
2006 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 65, no 6, 816-819 p.Article in journal (Refereed) Published
Abstract [en]

Background: Animal studies have indicated that 5-HT2A receptors could play a role in arthritic diseases.                             

Objective: To analyse the binding properties of 5-HT2A receptors in patients with rheumatoid arthritis.                             

Methods: Using a radioactive binding assay, 43 patients with rheumatoid arthritis were compared with 49 sex and age matched controls for density and affinity (measured as Bmax and Kd) of 5-HT2A serotonin receptors. Genotyping, using polymerase chain reaction, was undertaken to exclude the possibility that differences in the genetic polymorphism T102C for the 5-HT2A receptor determine differences in receptor density.                             

Results: Mean of Bmax of 5-HT2A receptors in rheumatoid patients was significantly lower than in controls, at 45.3 v 57.4 fmol/mg protein (p = 0.004), but there was no significant difference in Kd. The T102C receptor polymorphism genotypes showed a skewed distribution between the two groups. Even when adjusted for this, there was a significant difference in Bmax between the groups.                             

Conclusions: The density of 5-HT2A serotonin receptors in patients with rheumatoid arthritis is markedly reduced. This could either reflect a difference involved in the susceptibility to the disease or be a secondary effect of the disease.                             

Keyword
Aged, Arthritis; Rheumatoid/*metabolism, Binding; Competitive, Case-Control Studies, Female, Genotype, Humans, Male, Middle Aged, Polymorphism; Genetic, Radioligand Assay/methods, Receptor; Serotonin; 5-HT2A/*analysis/genetics
National Category
Social and Clinical Pharmacy
Identifiers
urn:nbn:se:umu:diva-14157 (URN)10.1136/ard.2005.042473 (DOI)16699051 (PubMedID)
Available from: 2007-11-29 Created: 2007-11-29 Last updated: 2017-12-14Bibliographically approved
2. Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis
Open this publication in new window or tab >>Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis
Show others...
2008 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 67, no 8, 1111-1115 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To analyse the association between the genetic polymorphisms within the HTR2A gene for the serotonin receptor and rheumatoid arthritis (RA).

METHODS: HTR2A gene polymorphisms were analysed in patients with RA and controls from two study populations using PCR based restriction endonuclease mapping or TaqMan allelic discrimination with more than 4000 individuals included in the current study.

RESULTS: At the discovery stage we detected significant differences in frequency of rs6313 (T102C polymorphism) between the patients with RA and controls (p = 0.006). Following validation with an extended set of single nucleotide polymorphisms (SNPs) and number of DNA samples, a trend in associations in allelic model for SNPs rs6314, rs1328674, rs6313 and rs6311 (p = 0.006, 0.002, 0.006, 0.009) was seen, although it was lost after correction for multi-comparison for all but rs1328674 (empirical p value = 0.021). However, haplotype frequency analysis based on these four SNPs showed significantly low representation of TCTT combination in patients with RA in comparison with controls (3.6% and 5.6%, p<0.001 on chi(2) test, empirical p = 0.004 after 100 000 permutations) and a significantly higher frequency of CTCC combination in patients with RA in comparison with controls (3.6% and 2.2%, p = 0.002 on chi(2) test, empirical p = 0.022 after 100 000 permutations).

CONCLUSIONS: In our study, genetic polymorphisms at the HTR2A gene are associated with susceptibility for RA, suggesting possible links between the serotonergic system and development of the disease.

National Category
Social and Clinical Pharmacy
Identifiers
urn:nbn:se:umu:diva-25995 (URN)10.1136/ard.2007.074948 (DOI)18006541 (PubMedID)
Available from: 2009-09-17 Created: 2009-09-17 Last updated: 2017-12-13Bibliographically approved
3. Association between the use of serotonin receptor 2A-blocking antidepressants and joint disorders
Open this publication in new window or tab >>Association between the use of serotonin receptor 2A-blocking antidepressants and joint disorders
2009 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 61, no 10, 1322-1327 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: There are case reports about antidepressants causing arthritis and arthralgia, and the majority of these reports deal with atypical antidepressants, which are serotonin receptor 2A (5-HT(2A))-blocking substances. The aim of this study was to examine a possible association between joint disorders and the use of 5-HT(2A)-blocking atypical antidepressants.

METHODS: We performed a retrospective study using reports of adverse drug reactions (ADRs) of 5-HT(2A)-blocking atypical antidepressant substances concerning joint disorders reported to the Swedish Adverse Drug Reactions Committee and the World Health Organization (WHO) Adverse Reactions Database during the period January 1, 1990 to December 31, 2006. The reports of joint disorders were related to sales figures measured as defined daily doses and to the total number of ADR reports.

RESULTS: In the Swedish material, the 5-HT(2A) antagonists were 45 times more often reported to give joint ADRs when related to sales figures and compared with the selective serotonin reuptake inhibitors (SSRIs; P < 0.001). Joint disorders constituted 6.6% of the total number of reports of possible ADRs for the three 5-HT(2A)-blocking substances mianserin, mirtazapine, and nefazodone compared with 0.5% for the SSRIs (P < 0.001). In the WHO material, the joint disorders constituted 1.3% of all ADRs for the 5-HT(2A)-blocking antidepressants and 0.6% for the SSRIs (P < 0.001).

CONCLUSION: In this study, joint disorders were considerably more frequently reported ADRs of 5-HT(2A)-blocking antidepressants than of other comparable drugs, suggesting a possible association between the use of 5-HT(2A)-blocking antidepressants and joint disorders.

National Category
Social and Clinical Pharmacy
Identifiers
urn:nbn:se:umu:diva-30604 (URN)10.1002/art.24673 (DOI)19790123 (PubMedID)
Available from: 2010-01-08 Created: 2010-01-08 Last updated: 2017-12-12Bibliographically approved
4. Glucocorticoid treatment increases density of serotonin 5-HT2A receptors in humans
Open this publication in new window or tab >>Glucocorticoid treatment increases density of serotonin 5-HT2A receptors in humans
2012 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 7, 1014-1020 p.Article in journal (Refereed) Published
Abstract [en]

Background: Interactions between the serotonergic system and the hypothalamic–pituitary–adrenal axis have been suggested, albeit the details for such interactions have yet to be established. Animal studies have shown that the density of serotonin 5-HT2A receptors is increased after administration of exogenous glucocorticoids.

Objective: The objective of this study was to explore possible changes in the pattern of density and affinity of 5-HT2A receptors in humans after treatment with glucocorticoids.

Methods: Using a radioactive binding assay, the density and affinity (measured as Bmax and Kd) of 5-HT2A serotonin receptors were measured in blood samples drawn from 27 individuals diagnosed with polymyalgia rheumatica and/or giant cell arteritis before and after start of an oral treatment with prednisolone. For each patient Bmax and Kd at baseline before prednisolone treatment were compared with Bmax and Kd in samples drawn at a first and second follow-up clinic visit at an average of 8.8 (±2.5) days and 33.6 (±6.8) days, respectively.

Results: The density of 5-HT2A receptors increased after treatment in 23 individuals. The mean Bmax value at baseline for all patients was 45.2 fmol/mg protein compared with 64.9 fmol/mg protein in the corresponding samples drawn at the second follow-up visit (p = 0.001). There also was an association between individuals accumulated prednisolone dose and the magnitude of change in Bmax between baseline and the first follow-up visit. Erythrocyte sedimentation rate, platelet count or gender had no influence on the results. There were no significant differences in Kd during the treatment period. However, a low Kd value at baseline was a predictor for an increase in Bmax following treatment.

Conclusions: The results of this study showed that the density of 5-HT2A serotonin receptors in man is increased after a subchronic treatment with glucocorticoids. The magnitude of the increase appears to be associated with the affinity of 5-HT2A receptors before treatment and the accumulated dose of glucocorticoid early in the treatment period.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Serotonin receptor 5-HT2A, Glucocorticoids, Prednisolone
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-64065 (URN)10.1016/j.psyneuen.2012.10.006 (DOI)000320412400007 ()
Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06Bibliographically approved

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