The phamacotherapy of depression has reduced morbidity and improved outcome for many depressive patients. A wide range of classical and new antidepressants are available for their treatment. However, 30-40% of all patients do not respond sufficiently to the initial treatment and present adverse effects. Pharmacogenetics studies the genetic basis of an individual's ability to respond to pharmacotherapy. Recently, some reports on serotonin transporter gene polymorphisms and their influence on the response to antidepressive therapy provide an interesting diagnostic tool in assessing the chances of response to antidepressants. We also investigated the relationship between serotonin transprter polymorphisms(5-HTTLPR) and the long-term effect of the antidepressant treatment. 128 depressive patients were enrolled into 2nd year study. The therapeutic response of each subset was not different at 8th, 16th week. but the subset with homozygote(l/l) of long variant showed a better therapeutic response to antidepressant than the heterozygote(l/s) of long and short variant, which showed a better therapeutic response than the subset with homozygote(s/s) of short variant at 1st year and 2nd year after the antidepressant treatment. This result shows that the serotonin transporter polymorphisms may be related to the long-term effect of antidepressant treatment. The potential for pharmacogenomics. the use of genetic increasing attention pharmacogenomics will contribute to individualize drug choice by using genotype to predict positive clinical outcomes, adverse reactions, and levels of drug metabolism. Personalized medicine the use of marker-assisted diagnosis and targeted therapies derived from an individual molecular profile, will impact the antidepressant therapy and this approach will replace the traditional trial-and-error practice of medicine.
Antidepressive Agents ; Depression ; Depressive Disorder* ; Diagnosis ; Drug Therapy ; Genotype ; Humans ; Precision Medicine ; Metabolism ; Pharmacogenetics* ; Serotonin ; Serotonin Plasma Membrane Transport Proteins

BACKGROUNDTo evaluate whether serotonin (5-HT), 5-HT2A receptor (5-HT2AR), and 5-HT transporter (serotonin transporter [SERT]) are associated with different disease states of depression, myocardial infarction (MI) and MI co-exist with depression in Sprague-Dawley rats.

METHODSAfter established the animal model of four groups include control, depression, MI and MI with depression, we measured 5-HT, 5-HT2AR and SERT from serum and platelet lysate.

RESULTSThe serum concentration of 5-HT in depression rats decreased significantly compared with the control group (303.25 ± 9.99 vs. 352.98 ± 13.73; P = 0.000), while that in MI group increased (381.78 ± 14.17 vs. 352.98 ± 13.73; P = 0.000). However, the depression + MI group had no change compared with control group (360.62 ± 11.40 vs. 352.98 ± 13.73; P = 0.036). The changes of the platelet concentration of 5-HT in the depression, MI, and depression + MI group were different from that of serum. The levels of 5-HT in above three groups were lower than that in the control group (380.40 ± 17.90, 387.75 ± 22.28, 246.40 ± 18.99 vs. 500.29 ± 20.91; P = 0.000). The platelet lysate concentration of 5-HT2AR increased in depression group, MI group, and depression + MI group compared with the control group (370.75 ± 14.75, 393.47 ± 15.73, 446.66 ± 18.86 vs. 273.66 ± 16.90; P = 0.000). The serum and platelet concentration of SERT in the depression group, MI group and depression + MI group were all increased compared with the control group (527.51 ± 28.32, 602.02 ± 23.32, 734.76 ± 29.59 vs. 490.56 ± 16.90; P = 0.047, P = 0.000, P = 0.000 in each and 906.38 ± 51.84, 897.33 ± 60.34, 1030.17 ± 58.73 vs. 708.62 ± 51.15; P = 0.000 in each).

CONCLUSIONSThe concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression. Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.

Animals ; Depression ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Male ; Myocardial Infarction ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2A ; metabolism ; Serotonin ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; metabolism

AIMTo determine the feasibility of establishing the heterologous expression model of human- serotonin transporter(hSERT or 5-HTT).

METHODScRNA of SERT was transcribed from cDNA, which was cloned in the pOTV vector. Each oocyte of mature xenopus laevis was injected with transcribed cRNA in vivo and incubated at room temperature for 4-9 days. Recording the current induced by 5-HT with voltage clamp technique tested the function of the expressed 5-HT transporter.

RESULTSThe transporter current could be observed in Ringer's solution containing 5-HT, and the 5-HT induced current were concentration-dependent. Norepinephrine and dopamine could not induce the transporter current while the 5-HT induced current could be specifically inhibited by 5-HTT blocker, desipramine.

CONCLUSIONThe results demonstrate that the heterologous expression product in xenopus laevis oocytes is human 5-HT transporter.

Animals ; Carrier Proteins ; genetics ; DNA, Complementary ; genetics ; Female ; Gene Expression ; Models, Animal ; Oocytes ; metabolism ; RNA, Messenger ; genetics ; Serotonin ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; biosynthesis ; genetics ; Xenopus laevis

Many studies showed abnormal serotonin transporter (5-HTT) function and heart rate variability (HRV) in panic disorder patients. The present study investigated the relationship between HRV power spectral analysis findings and platelet serotonin uptake in panic disorder patients. Short-term HRV over 5 min and platelet serotonin transporter uptake parameters (V(max) and K(m)) were measured both in 45 patients with panic disorder and in 30 age-matched normal healthy control subjects. Low frequency power (LF) normalized unit (nu) and LF/high frequency power (HF) were significantly higher, whereas HF and HF nu were lower in the patient group than in the control group. V(max) and K(m) were all significantly lower (i.e., reflects decreased 5-HTT function) in patients with panic disorder than in normal controls. In the patient group, Km was negatively correlated with LF/HF and LF nu whereas no such correlations between them were found in the control group. By multivariate analysis based on multiple hierarchical linear regression, a low Km independently predicted an increased LF nu even after controlling for age, sex, and body mass index in the patient group. These results suggest that impaired 5-HTT function is closely related to dysregulation of autonomic nervous system in panic disorder.
Adult ; Female ; Heart Rate/*physiology ; Humans ; Male ; Middle Aged ; Panic Disorder/*physiopathology ; Serotonin/metabolism ; Serotonin Plasma Membrane Transport Proteins/*metabolism ; Young Adult

In order to improve the efficiency of drug screening on serotonin transporter (SERT) inhibitors, a high-throughput screening (HTS) model is established in RBL-2H3 cells. The RBL-2H3 cells are very similar to the serotonin genetic neuro, in modulation of post-receptor mechanisms and transduction pathway of SERT reactivated. Depending on a fluorescence substrate ASP+ used in detection method of inhibitor rates, it's convenient, quick, accurate and effective, not making the environmental biohazard compared with radioactive experiments. Furthermore, biological screening model combined with computer aided virtual screening technique describing high-throughput virtual screening (HTVS). Bayesian classification method and molecular fingerprint similarity were applied to virtual screening technique, for screening compounds in compound library. Some compounds have been found, and then validated further by biological screening model. Combination of HTS and HTVS improves the efficiency of screening SERT inhibitors.
Animals ; Bayes Theorem ; Cell Line ; Drug Evaluation, Preclinical ; High-Throughput Screening Assays ; Models, Biological ; Rats ; Serotonin Plasma Membrane Transport Proteins ; metabolism ; Serotonin Uptake Inhibitors ; pharmacology

BACKGROUND: Use of antidepressant medications has been linked to detrimental impacts on bone mineral density and osteoporosis; however, the cellular basis behind these observations remains poorly understood. The effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. In this study, we hypothesized that antidepressants have a class- and dose-dependent effect on mesenchymal stem cell (MSC) differentiation, which may affect bone metabolism. METHODS: Human MSCs (hMSCs) were committed to differentiate when either adipogenic or osteogenic media was added, supplemented with five increasing concentrations of amitriptyline (0.001–10 µM), venlafaxine (0.01–25 µM), or fluoxetine (0.001–10 µM). Alizarin red staining (mineralization), alkaline phosphatase (osteoblastogenesis), and oil red O (adipogenesis) assays were performed at timed intervals. In addition, cell viability was assessed using a MTT. RESULTS: We found that fluoxetine had a significant inhibitory effect on mineralization. Furthermore, adipogenic differentiation of hMSC was affected by the addition of amitriptyline, venlafaxine, and fluoxetine to the media. Finally, none of the tested medications significantly affected cell survival. CONCLUSIONS: This study showed a divergent effect of three antidepressants on hMSC differentiation, which appears to be independent of class and dose. As fluoxetine and amitriptyline, but not venlafaxine, affected both osteoblastogenesis and adipogenesis, this inhibitory effect could be associated to the high affinity of fluoxetine to the serotonin transporter system.
Adipogenesis ; Alkaline Phosphatase ; Amitriptyline ; Antidepressive Agents ; Bone Density ; Cell Survival ; Fluoxetine ; Humans ; Mesenchymal Stromal Cells ; Metabolism ; Miners ; Osteoblasts ; Osteoporosis ; Serotonin Plasma Membrane Transport Proteins ; Venlafaxine Hydrochloride

OBJECTIVETo explore the mechanism and efficiency of Changji'an (CJA) in treating irritable bowel syndrome through studying the relationship between serotonin transporter (SERT) and visceral hypersensitivity in rats.

METHODSMale SD rats were randomly divided into 4 groups: the normal control group, the model group, the high-dosage and low-dosage CJA (CJAH and CJAL) groups. Visceral hypersensitivity model was established by colorectal distension. Normal saline and different doses of CJA were administrated to rats respectively, starting from the 10th day of modeling for 10 days. After then, the abdominal withdrawal reflex (AWR) was scored for semi-quantitative estimation of visceral sensitivity, and tissues of brain and colon were harvested for detecting expressions of SERT and serotonin (5-HT) with Western blot, real-time PCR and immunohistochemistry.

RESULTSAs compared with the normal controls, in model rats, the AWR score and content of 5-HT in intestinal mucosa were higher (P < 0.05), protein and mRNA expressions of SERT in colon and nucleus raphes dorsalis (NRD) were lower (P < 0.05), but all these indexes were improved significantly after CJA treatment, either in the CJAH or CJAL group (all P < 0.05). Besides, the number of 5-HT energic neuron in the model group and CJA groups was lower than that in the normal control group (P < 0.05).

CONCLUSIONCJA has therapeutic effect for improving visceral hypersensitivity in irritable bowel syndrome by way of regulating colonic expression of SERT and content of 5-HT.

Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Irritable Bowel Syndrome ; drug therapy ; genetics ; metabolism ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Serotonin ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; genetics ; metabolism ; Viscera ; drug effects ; metabolism

3,4-Methylenedioxymethamphetamine (MDMA) is a substituted amphetamine with stimulating and hallucinogenic properties. Since MDMA induces "ecstasy" it is extensively used as a "recreational" drug. It has been well established that MDMA is neurotoxic and can result in long-term degeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals in many species. The present study was undertaken to investigate the long-term neurotoxic effects of MDMA on cortical and hippocampal structures, by repeatedly administering MDMA in short time. Male Wistar rats were randomly assigned to control group and MDMA-treated group. MDMA (10 mg/kg) was administered to rats of MDMA-treated group, once per hour, total 40 mg/kg; rats of control group were treated with the same volume of saline. Thirty-two weeks after administering MDMA, the expression of serotonin transporter (SERT) mRNA and diazepam binding inhibitor (DBI) mRNA was detected by in situ hybridization. The expression of glial fibrillary acidic protein (GFAP) was detected by immunohistochemistry, and the degeneration of nerve terminals was demonstrated by Bielschowsky and Glee Marsland silver staining. The results showed that the expression of SERT mRNA in hippocampus decreased by 31.96%, while expression of DBI mRNA in neocortex increased by 40.51%, compared with the control group (P<0.05). The expression of GFAP in the brain tissue increased (P<0.05), while significant reduction of the nerve terminals in neocortex was demonstrated by silver staining, compared with the control group. These results suggest that the neurotoxicity of MDMA results in sustained cortical and hippocampal structural changes, which in turn result in disorder of the brain functions.
Animals ; Cerebral Cortex ; pathology ; physiopathology ; Diazepam Binding Inhibitor ; genetics ; metabolism ; Hippocampus ; pathology ; physiopathology ; Male ; N-Methyl-3,4-methylenedioxyamphetamine ; toxicity ; Neurotoxicity Syndromes ; etiology ; pathology ; physiopathology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Wistar ; Serotonin Plasma Membrane Transport Proteins ; genetics ; metabolism

BACKGROUNDOur previous studies have demonstrated that the levels of 5-hydroxytryptamine (5-HT) and 5-HT 2A receptor (5-HT2AR) in serum and platelet were associated with depression and myocardial infarction (MI), and pretreatment with ginseng fruit saponins (GFS) before MI and depression had an effect on the 5-HT system. In this study, the effects of GFS on the 5-HT system in the Sprague-Dawley (SD) rats with MI, depression, and MI + depression were evaluated.

METHODSA total of eighty SD rats were allocated to four groups: MI, depression, MI + depression, and control groups (n = 20 in each group). Each group included two subgroups (n = 10 in each subgroup): Saline treatment subgroup and GFS treatment subgroup. The levels of 5-HT, 5-HT2AR, and serotonin transporter (SERT) were quantified in serum, platelet lysate, and brain tissue through the enzyme-linked immunosorbent assay method, respectively.

RESULTSCompared with those in the saline treatment subgroups, the levels of 5-HT in serum and platelet lysate statistically significantly increased in the GFS treatment subgroups of MI, depression, and MI + depression groups (serum: all P = 0.000; platelet lysate: P = 0.002, 0.000, 0.000, respectively). However, the 5-HT levels in brain homogenate significantly decreased in the GFS treatment subgroups compared with those in the saline treatment subgroups in MI and depression groups (P = 0.025 and 0.044 respectively), and no significant difference was observed between saline and GFS treatment subgroups in MI + depression group (P = 0.663). Compared with that in GFS treatment subgroup of control group, the 5-HT2AR levels in the platelet lysate significantly decreased in GFS treatment subgroups of MI, depression, and MI + depression groups (all P = 0.000). Compared to those in the saline treatment subgroups, the serum SERT levels significantly decreased in the GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.009, 0.038, and P = 0.001, respectively), while the SERT levels of platelet lysate significantly decreased in GFS treatment subgroup of MI group (P = 0.000), significantly increased in GFS treatment subgroup of depression group (P = 0.019), and slightly changed in GFS treatment subgroup of MI + depression group (P = 0.219). No significant changes for SERT levels in brain homogenate could be found between the saline and GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.421, 0.076 and P = 0.642).

CONCLUSIONSThis study indicated that GFS might inhibit the reuptake of 5-HT from serum to platelet according to decreased 5-HT2AR in platelet and SERT in serum and platelet. The change of 5-HT in serum after GFS treatment was inconsistent with that in the brain. It seemed that GFS could not pass through the blood-brain barrier to affect the central serotonergic system.

Animals ; Blood-Brain Barrier ; drug effects ; metabolism ; Depression ; drug therapy ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Myocardial Infarction ; drug therapy ; Panax ; chemistry ; Rats ; Rats, Sprague-Dawley ; Receptor, Serotonin, 5-HT2B ; metabolism ; Saponins ; chemistry ; therapeutic use ; Serotonin ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; metabolism

Compounds with serotonin reuptake inhibition/5-HT(1A) dual activity were used to build 3D pharmacophore model as a training molecules by Discover Studio. Based on the model, 8 novel aryl piperazine benzo[b][1,4] oxazine derivatives were designed and synthesized, and their structures were confirmed by 1H NMR and HR-MS. Biological evaluation illustrated that compounds VI(1) and VI(7) showed potent functional activities at both 5-HT transporter and 5-HT(1A) receptor, which can be used as lead compounds to guide future research of design and synthesis of potent novel compounds.
Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Drug Design ; Genetic Vectors ; Molecular Structure ; Oxazines ; chemical synthesis ; chemistry ; pharmacology ; Piperazines ; chemical synthesis ; chemistry ; pharmacology ; Plasmids ; Protein Binding ; Receptor, Serotonin, 5-HT1A ; genetics ; metabolism ; Serotonin Plasma Membrane Transport Proteins ; genetics ; metabolism ; Serotonin Uptake Inhibitors ; metabolism ; Structure-Activity Relationship ; Transfection