Constitutive Serotonin Tone Modulates Molecular and Behavioral Response to Chronic Fluoxetine Treatment: A Study on Genetic Rat Model

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for the treatment of mood disorders. Yet, individual response to SSRIs is highly variable, with only a portion of patients showing the desired therapeutic effect. To better understand the molecular basis underlying individual variability in response to SSRIs, here we comparatively studied behavioral and molecular consequences of chronic treatment with fluoxetine, a widely used SSRI, in two sublines of rats with constitutionally different serotonin (5HT) homeostasis: the high-5HT and low-5HT sublines. Platelet 5HT levels, a recognized indicator of SSRI efficacy, were decreased by fluoxetine treatment in both 5HT-sublines. On the other hand, biologically active plasma 5HT levels were reduced only in high-5HT rats. The anxiolytic effect of fluoxetine was also evident only in high-5HT rats, as supported by spatio-temporal and ethological behavioral measures in the elevated plus maze (EPM) test and exploratory behavior measures in the open field (OF) test. None of the behavioral EPM or OF measures were significantly altered by fluoxetine treatment in low-5HT rats. Unexpectedly, 5HT levels in cerebral cortices tended to be reduced only in low-5HT rats. Moreover, the effects of fluoxetine on cortical expression levels of 5HT-related proteins were also present only in low-5HT rats, with serotonin transporter (5HTT) and serotonin receptor type 1a (Htr1a) being down-regulated, while serotonin receptor type 4 (Htr4) was up-regulated by fluoxetine treatment. The obtained results support a role of individual 5HT tone as an important influencing factor on the biological actions of SSRI antidepressants.

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Psychiatric pharmacogenomic testing in clinical practice

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2010.12.1/dmrazek ◽

2010 ◽

Vol 12 (1) ◽

pp. 69-76 ◽

Cited By ~ 2

Keyword(s):

Cytochrome P450 ◽

Clinical Practice ◽

Serotonin Receptor ◽

Selective Serotonin Reuptake Inhibitors ◽

Target Genes ◽

European Ancestry ◽

Cytochrome P450 2D6 ◽

Drug Metabolizing Enzyme ◽

Ultrarapid Metabolizers ◽

P450 2D6

The clinical adoption of psychiatric pharmacogenomic testing has taken place rapidly over the past 7 years. Initially, drug-metabolizing enzyme genes, such as the cytochrome P450 2D6 gene (CYP2D6), were identified. Genotyping the highly variable cytochrome P450 2D6 gene now provides clinicians with the opportunity to identify both poor metabolizers and ultrarapid metabolizers of 2D6 substrate medications. Subsequently, genes influencing the pharmacodynamic response of medications have been made available for clinical practice. Among the earliest "target genes" was the serotonin transporter gene (SLC6A4) which has variants that have been shown to influence the clinical response of patients of European ancestry when they are treated with selective serotonin reuptake inhibitors. Genotyping of some of the serotonin receptor genes is also available to guide clinical practice. The quantification of the clinical utility of pharmacogenomic testing is evolving, and ethical considerations for testing have been established. Given the increasingly clear cost-effectiveness of genotyping, it has recently been predicted that pharmacogenomic testing will routinely be ordered to guide the selection and dosing of psychotropic medications.

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Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML

Scientific Reports ◽

10.1038/s41598-018-32306-4 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 1

Author(s):

Antònia Banús-Mulet ◽

Amaia Etxabe ◽

Josep Maria Cornet-Masana ◽

Miguel Ángel Torrente ◽

María Carmen Lara-Castillo ◽

...

Keyword(s):

Therapeutic Target ◽

Serotonin Receptor ◽

Receptor Type

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Genetic Background Underlying 5-HT1A Receptor Functioning Affects the Response to Fluoxetine

International Journal of Molecular Sciences ◽

10.3390/ijms21228784 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8784

Author(s):

Elena M. Kondaurova ◽

Alexander Ya. Rodnyy ◽

Tatiana V. Ilchibaeva ◽

Anton S. Tsybko ◽

Dmitry V. Eremin ◽

...

Keyword(s):

Genetic Background ◽

Selective Serotonin Reuptake Inhibitors ◽

Tryptophan Hydroxylase ◽

Forced Swim Test ◽

Receptor Protein ◽

Mrna Levels ◽

Tryptophan Hydroxylase 2 ◽

Protein Levels ◽

Receptor Mrna ◽

Fluoxetine Treatment

The influence of genetic background on sensitivity to drugs represents a topical problem of personalized medicine. Here, we investigated the effect of chronic (20 mg/kg, 14 days, i.p.) antidepressant fluoxetine treatment on recombinant B6-M76C mice, differed from control B6-M76B mice by CBA-derived 102.73–110.56 Mbp fragment of chromosome 13 and characterized by altered sensitivity of 5-HT1A receptors to chronic 8-OH-DPAT administration and higher 5-HT1A receptor mRNA levels in the frontal cortex and hippocampus. Significant changes in the effects of fluoxetine treatment on behavior and brain 5-HT system in recombinant B6-M76C mice were revealed. In contrast to B6-M76B mice, in B6-M76C mice, fluoxetine produced pro-depressive effects, assessed in a forced swim test. Fluoxetine decreased 5-HT1A receptor mRNA levels in the cortex and hippocampus, reduced 5-HT1A receptor protein levels and increased receptor silencer Freud-1 protein levels in the hippocampus of B6-M76C mice. Fluoxetine increased mRNA levels of the gene encoding key enzyme for 5-HT synthesis in the brain, tryptophan hydroxylase-2, but decreased tryptophan hydroxylase-2 protein levels in the midbrain of B6-M76B mice. These changes were accompanied by increased expression of the 5-HT transporter gene. Fluoxetine reduced 5-HT and 5-HIAA levels in cortex, hippocampus and midbrain of B6-M76B and in cortex and midbrain of B6-M76C; mice. These data demonstrate that changes in genetic background may have a dramatic effect on sensitivity to classic antidepressants from the Selective Serotonin Reuptake Inhibitors family. Additionally, the results provide new evidence confirming our idea on the disrupted functioning of 5-HT1A autoreceptors in the brains of B6-M76C mice, suggesting these mice as a model of antidepressant resistance.

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ISO-CC-005: A phase I/II study of Modufolin (MTHF) in combination with 5-FU, irinotecan, and oxaliplatin ± bevacizumab in patients with metastasizing colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.838 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 838-838

Author(s):

Helena Anna Taflin ◽

Karin M E Ganlov ◽

Tormod Kyrre Guren ◽

Christos Papadimitrou ◽

Nikolaos K. Kentepozidis ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Active Form ◽

Metabolic Activation ◽

Individual Variability ◽

Biologically Active ◽

Chemotherapy Treatment ◽

Time To Death ◽

Dose Levels ◽

Clinical Trial Information

838 Background: Chemotherapy treatment of Colorectal Cancer, often include 5-Fluorouracil (5- FU). 5-FU inhibits the enzyme thymidylate synthase (TS), stopping the supply of thymidine for DNA synthesis. 5-FU is always combined with a folate, which enhances the 5-FU effect. Marketed folates such as LV/L-LV are prodrugs needing enzymatic conversion. Modufolin is the natural, biologically active form of the folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability Methods: ISO-CC-005 is a multi-center, phase I/II study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. The study investigates safety and tolerability of Modufolin at 4 dose levels by analysing the number and severity of AEs, SAEs and DLTs. Efficacy is evaluated as ORR after four cycles of chemotherapy. Gene expression, deoxyuridine levels as an indirect marker of TS inhibition and time to death is also investigated. Three to six patients per cohort are included. All receives Modufolin twice every two weeks during at least four cycles of chemotherapy. Results: Today, 42 patients have been enrolled and 40 have initiated treatment. 13 are 1st line patients, 16 are in 2nd line, 10 are in 3rd line and 1 is in 5th treatment line. 19 SAEs have been reported in 12 patients, 3 of these were judged as at least possibly related to Modufolin. No SAE were judged as solely related to Modufolin. 31 patients have today been evaluated for efficacy. ORR 1st line patients (n=12) All 50% (6 PR, 6 SD) Patients with Modufolin dose ≥60 mg/m2 71% (5 PR, 2 SD) Patients with Modufolin dose ≥60 mg/m2 + oxaliplatin 100% (3 PR) Conclusions: The lack of need for metabolic activation makes Modufolin a better candidate than LV/L-LV for improved outcome of 5-FU-based chemotherapy regimens in mCRC. The ISO-CC-005 study evaluates Modufolin in combination with 5-FU, irinotecan, oxaliplatin ± bevacizumab in mCRC patients in 4 countries in Europe. The results, so far, for both safety and efficacy seems promising. Clinical trial information: NCT02244632.

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Direct interaction of the resistance to inhibitors of cholinesterase type 3 protein with the serotonin receptor type 3A intracellular domain

Journal of Neurochemistry ◽

10.1111/jnc.13578 ◽

2016 ◽

Vol 137 (4) ◽

pp. 528-538 ◽

Cited By ~ 8

Author(s):

Sita Nirupama Nishtala ◽

Nelli Mnatsakanyan ◽

Akash Pandhare ◽

Chun Leung ◽

Michaela Jansen

Keyword(s):

Serotonin Receptor ◽

Direct Interaction ◽

Receptor Type ◽

Intracellular Domain ◽

Type 3

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Dental Fluorosis: Its Use as a Biomarker

Advances in Dental Research ◽

10.1177/08959374940080010201 ◽

1994 ◽

Vol 8 (1) ◽

pp. 105-110 ◽

Cited By ~ 51

Author(s):

P.K. Den Besten

Keyword(s):

Dental Fluorosis ◽

Biological Marker ◽

Epidemiological Studies ◽

Individual Variability ◽

Activity Level ◽

Individual Response ◽

Growth And Remodeling ◽

Nutritional Factors ◽

Fluoride Exposure ◽

The Relationship

Several epidemiological studies, beginning with those of Dean and co-workers in the 1940's, clearly demonstrate the relationship between dental fluorosis in humans and the level of fluoride in water supplies. These studies and others have shown that, in a population, there is a direct relationship among the degree of enamel fluorosis, plasma and bone fluoride levels, and the concentration of fluoride in drinking water. However, dental fluorosis is a reflection of fluoride exposure only during the time of enamel formation, somewhat limiting its use as a biomarker. In addition, the degree of fluorosis is dependent not only on the total fluoride dose, but also on the timing and duration of fluoride exposure. At the level of an individual response to fluoride exposure, factors such as body weight, activity level, nutritional factors, and the rate of skeletal growth and remodeling are also important. These variables, along with an individual variability in response to similar doses of fluoride, indicate that enamel fluorosis cannot be used as a biological marker of the level of fluoride exposure for an individual.

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The Association Between the Serotonin Receptor Type 1B (HTR1B) Gene rs13212041 Polymorphism and Trait Anxiety in China Han College Subjects

10.21203/rs.3.rs-345407/v1 ◽

2021 ◽

Author(s):

Xiaofei Ruan ◽

Suwen Fang ◽

qi zheng ◽

Senqing Qi ◽

Yingfang Tian ◽

...

Keyword(s):

Emotional Disorders ◽

Trait Anxiety ◽

Gene Polymorphisms ◽

Serotonin Receptor ◽

Protective Factor ◽

Receptor Type ◽

Personality Factor ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Development Of Anxiety

Abstract Trait anxiety is a vulnerable personality factor for anxiety and depression. High levels of trait anxiety confer elevated risk for the development of anxiety and other psychiatric disorders. There is evidence that serotonin receptor type 1B (5-HT1B) gene polymorphisms play an important role in emotional disorders. Genotyping for four single-nucleotide polymorphisms (SNP) (rs11568817, rs130058, rs6297 and rs13212041) was conducted for 388 high trait-anxious (HTA) individuals and 463 low trait-anxious (LTA) individuals in China Han college subjects. The results showed that the frequency of the C-allele and TC+CC genotype in rs13212041 in the LTA individuals was higher than that in the HTA individuals (p = 0.025 and p = 0.014, respectively). Both the C-allele and TC+CC genotype were associated with trait anxiety decreasing (OR = 0.771 and OR = 0.71, respectively). Furthermore, different gene models analysis also showed that the C allele is a protective factor in trait anxiety in Chinese Han college subjects. These findings suggest that the variance in 5-HT1B gene polymorphisms may play a role in trait anxiety in China Han college subjects. The rs13212014 polymorphism may be involved in decreasing the risk of trait anxiety. These results also provide a novel insight into the molecular mechanism about trait anxiety.

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Intervention in Neuropsychiatric Disorders by Suppressing Inflammatory and Oxidative Stress Signal and Exploration of In Silico Studies for Potential Lead Compounds from Holigarna caustica (Dennst.) Oken leaves

Biomolecules ◽

10.3390/biom10040561 ◽

2020 ◽

Vol 10 (4) ◽

pp. 561 ◽

Cited By ~ 7

Author(s):

Md. Adnan ◽

Md. Nazim Uddin Chy ◽

A.T.M. Mostafa Kamal ◽

Kazi Asfak Ahmed Chowdhury ◽

Md. Atiar Rahman ◽

...

Keyword(s):

Serotonin Receptor ◽

Antioxidant Activities ◽

Condensed Tannin ◽

Folk Medicine ◽

Reducing Power ◽

Anxiolytic Effect ◽

Neuropsychiatric Disorders ◽

In Silico Studies

Holigarna caustica (Dennst.), a popular plant used in folk medicine in Bangladesh, is often used by the local folk practitioner to treat a variety of chronic diseases. The present research is an attempt to find out an innovative therapeutic prospect for the management of neuropsychiatric disorders. The methanol extract of H. caustica leaves (MEHC) were utilized on various behavioral tests for assessing anxiolytic, anti-depressant, and anti-inflammatory activities. The antioxidant potentials and quantitative phytochemicals were evaluated through spectrophotometric methods. Results revealed that treatment of MEHC (200 and 400 mg/kg) significantly reduced anxiety like behaviors in mice, particularly, 400 mg/kg efficiently improved % of entries and time spent (p < 0.05) in the open arms in elevated plus maze test, whereas, superior head dipping tendency (p < 0.05) was observed in hole-board test. In contrast, mice treated with 200 mg/kg revealed better anxiolytic effect in both open field and hole-cross tests. During antidepressant evaluation, mice administrated with MEHC exhibited active behaviors (swimming and struggling) in forced swimming and tail suspension tests. In parallel, MEHC manifested a noteworthy (p < 0.001) suppression of inflammatory response induced by histamine. The MEHC also showed strong antioxidant activities in 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) (IC50: 57.64 μg/mL) scavenging, H2O2 (IC50: 51.60 μg/mL) scavenging, and ferric reducing power assay. The levels of total phenol, flavonoid, flavonol, condensed tannin, and antioxidant were estimated as higher in MEHC. Moreover, 11 compounds were documented as bioactive, displayed good binding affinities to potassium channel receptor, human serotonin receptor, cyclooxygenase (COX-1 and 2), and xanthine oxidoreductase enzyme targets in molecular docking experiments. Furthermore, ADME/T and Prediction of Activity Spectra for Substances (PASS) analyses exposed their drug-likeness, nontoxic upon consumption, and likely pharmacological actions. Overall, the H. caustica is potentially bioactive as evident by in vivo, in vitro, and computational analysis. Our findings support the folkloric value of this plant, which may provide a potential source towards developing drug leads.

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