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Glucocorticoid treatment increases density of serotonin 5-HT2A receptors in humans
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
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. Vol. 38, no 7, 1014-1020 p.
Keyword [en]
Serotonin receptor 5-HT2A, Glucocorticoids, Prednisolone
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-64065DOI: 10.1016/j.psyneuen.2012.10.006ISI: 000320412400007OAI: oai:DiVA.org:umu-64065DiVA: diva2:587110
Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06Bibliographically approved
In thesis
1. 5-HT2A: a serotonin receptor with a possible role in joint diseases
Open this publication in new window or tab >>5-HT2A: a serotonin receptor with a possible role in joint diseases
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
5-HT2A serotonin receptor, serotonin, rheumatoid arthritis, adverse drug reaction, HTR2A, glucocorticoids
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:umu:diva-64013 (URN)978-91-7459-549-9 (ISBN)
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

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Kling, AndersMjörndal, TomRantapää-Dahlqvist, Solbritt

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