Serotonin Reuptake Research Articles

Comparing pharmacotherapy and transcranial magnetic stimulation for the treatment of anxiety and depression after aortic dissection surgery.

Aortic coarctation is a potentially fatal condition that is primarily treated surgically. Despite successful procedures, patients frequently experience postoperative anxiety and depression, which can hinder recovery and worsen outcomes. Pharmacological interventions, such as 5-hydroxytryptamine (5-HT) and norepinephrine reuptake inhibitors, are commonly prescribed; however, their efficacy alone or in combination with non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (TMS), remains unclear. To assess the effect of medications and TMS on post-aortic surgery anxiety and depression. We analyzed the outcomes of 151 patients with anxiety and depression who were hospitalized for aortic dissection between January 2020 and September 2022. Using the random number table method, 75 and 76 patients were allocated to the normal control and study groups, respectively. All the patients were treated using routine procedures. The control group was administered anti-anxiety and anti-depression drugs, whereas the study group was treated with TMS in addition to these medications. The patients in both groups showed improvement after two courses of treatment. The Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Scale (HAMD) were used to assess anxiety and depression, respectively. The serum levels of brain-derived neurotrophic factor (BDNF) and 5-HT were determined using enzyme-linked immunosorbent assay. The Pittsburgh Sleep Quality Index (PSQI) was used to estimate sleep quality, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function. The HAMD and HAMA scores reduced in 2 groups, with the study group achieving a lower level than control (P < 0.05). In the control group, 43 patients recovered, 17 showed improvement, and 15 were deemed invalid. In the study group, 52 recovered, 20 improved, and four were invalid. The efficacy rate in study group was 94.74% compared to 80.00% in control (P < 0.05). The BDNF and 5-HT levels increased in both groups, with higher levels observed in the experimental group (P < 0.05). Moreover, the PSQI scores decreased in 2 groups, but were lower in the intervention group than control (P < 0.05). The scores of the RBANS items increased, with the study group scoring higher than control (P < 0.05). Combining anti-anxiety and anti-depressive drugs with repetitive TMS after aortic surgery may enhance mood and treatment outcomes, offering a promising clinical approach.

Effects of dietary tryptophan levels on growth performance, serotonin metabolism, brain 5-HT and cannibalism activities in tiger puffer, Takifugu rubripes fingerlings

Essential amino acid (EAA) requirements of aquaculture fish species can be used as a guideline for commercial feed formulation. Several EAA requirements have been quantified in tiger puffer (Takifugu rubripes). However, as the third limiting amino acid (AA) of many plant protein sources, tryptophan requirement of this species has yet to be quantified. This study was conducted to determine dietary tryptophan requirement of tiger puffer, and investigate the effect of dietary tryptophan supplementation on the cannibalism, brain serotonin (5-hydroxytryptpamine, 5-HT) metabolism and serum cortisol levels. Six experimental diets were prepared using fish meal, gelatin and corn protein concentrate as intact protein, and then supplemented with crystalline AA premix. The analyzed tryptophan levels in the experimental diets were 3.5, 4.1, 4.5, 5.5, 7.0 and 11.8 g/kg of dry diet. Experimental diets were randomly fed in triplicate to tiger puffer (initial average weight of 17.5 g) for 58 days. The weight gain (WG), feed conversion ratio (FCR) and protein efficiency ratio (PER) were significantly affected by dietary tryptophan, and the break points were observed at 5.07, 4.82 and 4.99 g/kg of dry diet, respectively. Compared to the basal diet, the cannibalism (the rate of bite mark appearance) was significantly lower and survival rate was significantly higher when fish were given diets containing 7.0 and 11.8 g/kg tryptophan. The concentrations of free tryptophan and phenylalanine in the brain exhibited a nonlinear increase in response to the incremental levels of dietary tryptophan. Brain 5-HT concentration was significantly affected by dietary tryptophan levels, but did not show a significant dose-dependent response. The expression of genes related to 5-HT metabolism (tph1a, ddc and aldh) and serotonin reuptake (sert) in the brain varied significantly and exhibited a nonlinear relationship with the graded levels of dietary tryptophan. In addition, serum cortisol levels showed a decreasing trend till the 5.5 g/kg tryptophan inclusion level, at which point there appeared to be the lowest level. In conclusion, based on nonlinear regression analysis of the WG, FCR and PER, dietary tryptophan requirement of tiger puffer was determined to be range between 4.82 and 5.07 g/kg of dry diet (10.48–11.03 g/kg of dietary protein). Dietary tryptophan supplementation above requirement could mitigate cannibalism and improve the survival of tiger puffer, which may be attributed to regulating the synthesis and catabolism of 5-HT and its availability in the synaptic cleft, and subsequently the reduction of serum cortisol content.

Research Progress on the Basic Pharmacodynamic Substance and Mechanism of &lt;i&gt;Citri Sarcodactylis Fructus&lt;/i&gt; in Relieving Anxiety

Anxiety disorder resulting from the interaction of psychological factors-caused anxiety and mood disorder symptoms is one of the clinical mental diseases. Excessive worry, nervousness and fear often bring about several negative outcomes, and seriously impact the physical, mental, and social functioning of patients. What’s worse, with poor treatment, anxiety disorder may develop into mental illnesses such as depression and schizophrenia. The treatment of anxiety has mainly recourse to drug therapy and psychotherapy; however, Western drug therapy represented by 5-hydroxytryptamine reuptake inhibitor often causes evident adverse effects, including nausea and constipation, as well as poor long-term medication compliance of patients. Citri Sarcodactylis Fructus can sooth the liver and regulate qi, which can be applied to alleviate anxiety disorder as an ancillary drug. Modern pharmacological research revealed that bergamot volatile oil, also known as bergamot essential oil (BEO), is the main active chemical component of Citri Sarcodactylis Fructus for anti-anxiety. BEO has been confirmed to exert an anti-anxiety effect through modulating neuronendocrine-immune network, including immunoregulation, suppression of hyperactive hypothalamic-pituitary-adrenal (HPA) axis, enhancement of function of hypothalamic-pituitary-thyroid (HPT) axis, modulation of neurotransmitter, and promotion of neurotrophic effect. The study discusses the current research status regarding the application of Citri Sarcodactylis Fructus for anti-anxiety in recent years, and deeply probes into the mechanism of Citri Sarcodactylis Fructus playing an anti-anxiety role via neuronendocrine-immune network, in an effort to provide references to clinical treatment of anxiety disorder and new ideas for developing drugs targeting anxiety disorders.

Chronic dizziness: modern treatment methods taking into account comorbidity

In most cases, chronic dizziness is persistent postural perceptual dizziness (PPPD), which is often combined with other diseases of the vestibular system and anxiety disorders. In real-life clinical practice, PPPD and comorbid disorders are rarely diagnosed and effective treatments are rarely prescribed, so the development of modern methods for managing patients with PPPD with comorbid diseases is important.Objective: to analyze the typical management practices and evaluate the effectiveness of complex therapy in patients with PPPD and comorbid disorders.Material and methods. We examined 60 patients (mean age – 42.5±13.8 years) with diagnosis of PPPD (according to the diagnostic criteria of the Barany Society) and comorbid diseases. All patients were examined twice: at the beginning and after completion of treatment, which lasted an average of 1 month. Treatment included antidepressants (serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors), anti-anxiety medications, vestibular exercises, an educational program, and cognitive behavioral therapy. Arlevert (a combination of cinnarizine 20 mg + dimenhydrinate 40 mg) was used as a drug therapy for the treatment of vestibular dizziness in 28 patients. A clinical otoneurological evaluation and videonystagmography were performed to assess vestibular disorders; the severity of dizziness was assessed using an otoneurological questionnaire and the Dizziness Handicap Inventory (DHI); the Hospital Anxiety and Depression Scale (HADS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Spielberger Anxiety Inventory (STAI) were used to assess anxiety and depressive disorders.Results. None of the 60 patients had previously been diagnosed with PPPD. They were observed with a misdiagnosis of cerebrovascular disease and/or cervical spine pathology and received ineffective treatment. Anxiety and depressive disorders were detected in 32 (53.33%) patients, migraine – in 20 (33.33%) and previous peripheral vestibular disorders – in 8 (13.33%) patients. After one month of treatment in patients with PPPD and comorbid conditions, the severity of dizziness according to DHI decreased from 45.59±15.47 to 29.9±12.56 points (p&lt;0.001), the severity of anxiety according to BAI from 27.50±6.38 to 15.66±4.07 points (p&lt;0.001), the severity of depression according to BDI from 11.91±6.24 to 7.06±4.12 points (p&lt;0.001), the severity of anxiety according to HADS from 13.47±4.16 to 8.60±2.86 points (p&lt;0.001), the severity of depression according to HADS from 6.34±3.72 to 4.31±2.82 points (p&lt;0.001), situational anxiety according to STAI from 50.69±7.13 to 41.26±6.24 points (p&lt;0.001), personal anxiety according to STAI from 54.66±8.21 to 43.78±6.75 points (p&lt;0.001).Conclusion. It was found that PPPD is rarely diagnosed, and anxiety disorders, migraine and peripheral vestibular disorders are very common in PPPD patients. The integrated approach in the treatment of patients with PPPG, taking into account concomitant disorders, has demonstrated high efficacy.

Variety of Serotonin Levels in Pediatric Gastrointestinal Disorders.

(1) Serotonin primarily regulates our emotions. A complex process, which includes dysfunctions in gastrointestinal motility and deregulation of the gene responsible for serotonin reuptake (SERT), is implicated in the pathophysiology of irritable bowel syndrome (IBS). This also encompasses changes in intestinal microbiota, the response to stress, the intricate interplay between the brain and the digestive tract, heightened sensitivity to visceral stimuli, and low-grade inflammation. This paper aims to investigate the effectiveness of probiotic therapy in managing gastrointestinal and neuropsychiatric symptoms related to serotonin levels, with a focus on individuals with serotonin deficiency and those with normal serotonin levels experiencing gastrointestinal disorders. (2) The study involved 135 pediatric patients aged 5-18 years with gastrointestinal disturbances, including constipation, diarrhea, and other symptoms, such as nausea, flatulence, feeling full, or gastrointestinal pain. (3) Serotonin testing was performed, and administering probiotics appeared to be effective in addressing serotonin deficiency and other gastrointestinal disorders. (4) Serotonin's pivotal role in regulating neurotransmitter secretion and its impact on neuropsychiatric health, coupled with gender differences and age-related declines, underscore the complexity of their influence on gastrointestinal and neuropsychiatric conditions.

Identification of Serotonin Transporter Inhibitors from Selected Marine Alkaloids: A Molecular Docking and ADME Study

One of the common mental illnesses that affect people worldwide is depression. It can impact people from all backgrounds and age groups. Despite having medications for depression, very few people respond to it in an efficient manner. Currently used anti-depressants show side effects like urine retention, nausea, weight gain, cardiovascular disorders, etc. Natural compounds are being evaluated for their therapeutic potential to eradicate these side effects. Metabolites obtained from marine organisms possess diverse beneficial effects. Various sponges, corals, and seaweeds contain compounds with magical properties to heal mental disorders. This study demonstrates the molecular docking of serotonin transporter (SERT) with some marine alkaloids. Results generated from PyRx virtual screening software shows that out of thirteen selected alkaloids, only gelliusine A have a higher binding affinity than the prescribed anti-depressant paroxetine. According to SwissADME, most of the selected alkaloids showed better absorption, distribution, metabolism and excretion (ADME) properties. But gelliusine A has low gastrointestinal absorption and does not cross blood-brain barrier (BBB). Further optimization and experimental investigations of these compounds are needed to enhance their properties to become better anti-depressants against reuptake of serotonin.

Co-exposure to lead, mercury, and cadmium induces neurobehavioral impairments in mice by interfering with dopaminergic and serotonergic neurotransmission in the striatum.

Humans are exposed to lead (Pb), mercury (Hg), and cadmium (Cd) through various routes, including drinking water, and such exposure can lead to a range of toxicological effects. However, few studies have investigated the toxic effects of exposure to mixtures of metals, particularly in relation to neurotoxicity. In this study, 7-week-old male mice were exposed to Pb, Hg, and Cd individually or in combination through their drinking water for 28 days. The mice exposed to the metal mixture exhibited significantly reduced motor coordination and impaired learning and memory abilities compared to the control group and each of the single metal exposure groups, indicating a higher level of neurotoxicity of the metal mixture. The dopamine content in the striatum was significantly lower in the metal mixture exposure group than in the single metal exposure groups and the control group. Furthermore, compared to the control group, the metal mixture exposure group showed a significantly lower expression level of tyrosine hydroxylase (TH) and significantly higher expression levels of dopamine transporter (DAT), tryptophan hydroxylase 1 (TPH1), and serotonin reuptake transporter (SERT). Notably, there were no significant differences in SERT expression between the single metal exposure groups and the control group, but SERT expression was significantly higher in the metal mixture exposure group than in the single metal and control groups. These findings suggest that the key proteins involved in the synthesis and reuptake of dopamine (TH and DAT, respectively), as well as in the synthesis and reuptake of serotonin (TPH1 and SERT, respectively), play crucial roles in the neurotoxic effects associated with exposure to metal mixtures. In conclusion, this study demonstrates that simultaneous exposure to different metals can impact key enzymes involved in dopaminergic and serotonergic neurotransmission processes, leading to disruptions in dopamine and serotonin homeostasis and consequently a range of detrimental neurobehavioral effects.

Predictive capacity of FRAX in a spanish region with a hip fracture rate close to the national mean

BackgroundIt is known that standardized incidence rates of hip fracture vary among older people in Spain. So far, the results published on the validation of the FRAX® tool in Spain have suggested that the major osteoporotic fractures (MOFs) risk in our country is underestimated. These studies have practically been based on Spanish cohorts evaluated in Catalonia, a higher hip fracture rate area. The purpose of this study is to analyse the ability of the FRAX® in a Spanish mid-fracture rate population.MethodsStudy design: Retrospective cohort study.MeasuresMOFs: hip, humerus, wrist, spine fractures. Risk of fracture assessed by calculating odds ratios (ORs). Predictive capacity of FRAX® according to the osteoporotic fractures observed between 2009 and 2018 (ObsFr) to predicted by FRAX® without densitometry in 2009 (PredFr) ratio.Results285 participants (156 women, 54.7%) with a mean ± SD of 61.5 ± 14 years. Twenty-four people sustained 27 fractures (15 MOFs). Significant ORs were observed for an age ≥ 65 (2.92; 95% CI, 1.07–7.96), female sex (3.18; 95% CI, 1.24–8.16), rheumatoid arthritis (0.62; 95% CI, 2.03–55.55), proton pump (2.71; 95% CI, 1.20–6.09) and serotonin reuptake (2.51; 95% CI, 1.02–6.16) inhibitors. The ObsFr/PredFr ratio in women were 1.12 (95% CI, 0.95–1.29) for MOFs and 0.47 (95% CI, 0-0.94) for hip fractures. Men had a ratio of 0.57 (95% CI, 0.01–1.14) for MOF, no hip fractures were observed. The ratios for the overall group were 1.29 (95% CI, 1.12–1.48) for MOFs and 0.70 (95% CI, 0.22–1.17) for hip fractures.ConclusionsFRAX® accurately predicted MOFs in women population with a hip fracture incidence rate close to the national mean compared to previous studies conducted in higher incidence regions in Spain.

Tiaoqi Jieyu acupuncture for treatment-resistant depression: a randomized controlled trial

To observe the effect of Tiaoqi Jieyu (regulating qi and relieving depression) acupuncture on the clinical symptoms of treatment-resistant depression (TRD), and to explore the relationship between the acupuncture pain sensitivity and symptom's improvement. A total of 78 patients with TRD were randomly divided into an observation group (39 cases, 3 cases dropped off) and a control group (39 cases, 4 cases dropped off). The patients in the control group were treated with medications according to the treatment plan of psychiatrists (at least one medication was 5-hydroxytryptamine reuptake inhibitor). On the basis of the control group, the patients in the observation group were treated with Tiaoqi Jieyu acupuncture, and Baihui (GV 20), Yintang (GV 24+), Yanglingquan (GB 34), Taichong (LR 3), Hegu (LI 4), Neiguan (PC 6), Yinlingquan (SP 9) and Zusanli (ST 36), etc. were selected. The acupuncture was given three times a week. Both groups were treated for 8 weeks. After 8-week treatment, the response rate of Hamilton depression scale-24 (HAMD-24) score after was evaluated in the two groups. The scores of HAMD-24 and Hamilton anxiety scale (HAMA) were compared between the two groups before treatment, after 4, 8-week treatment and 12 weeks after treatment (follow-up). After the first treatment and 8-week treatment, the visual analogue scale (VAS) score in the observation group was evaluated, and the correlation between VAS score after the first treatment and HAMD-24 score before treatment, between VAS score after the first treatment and the course of disease in the observation group was analyzed, and the correlation between difference of VAS after 8-week treatment and after the first treatment and difference of HAMD-24 score before treatment and after 8-week treatment was analyzed. After 8-week treatment, the response rate of HAMD-24 score in the observation group was 52.8% (19/36), higher than 17.1% (6/35) in the control group (P<0.001). Compared before treatment, the scores of HAMD-24 and HAMA in the two groups were decreased after 4-week treatment, 8-week treatment and in follow-up (P<0.05), and those in the observation group were superior to the control group (P<0.05). After 8-week treatment, the acupuncture pain VAS score in the observation group was (5.28±2.13) points, which was higher than (3.33±1.62) points after the first treatment (P<0.001). There was a negative correlation between VAS score after the first treatment and HAMD-24 score before treatment in the observation group (r =-0.486, P=0.003); there was no correlation between acupuncture pain VAS score after the first treatment and the course of disease in the observation group (P>0.05). After 8-week treatment, there was a positive correlation between the difference of VAS score and the difference of HAMD-24 score in the observation group (r =0.514, P=0.001). Tiaoqi Jieyu acupuncture could improve the depression and anxiety in patients with TRD, and the symptom's improvement is related to the recovery of acupuncture pain sensitivity.

Vital function of DRD4 in dapoxetine medicated premature ejaculation treatment.

Recently, dapoxetine has been widely accepted to treat premature ejaculation by fast-inhibiting 5-hydroxytryptamine reuptake. However, dapoxetine is not suitable for all premature ejaculation patients in clinical treatment. We need to investigate and reveal the mechanism deeply to solve this problem. To investigate and reveal the function of dopamine D4 receptor in dapoxetine medicated premature ejaculation treatment. A rat model was used to screen rapid ejaculators. The molecular mechanisms of histone serotonylation-mediated regulation of dopamine D4 receptor were demonstrated by chromatin immunoprecipitation, DNA pull-down, mass spectrometry analysis, and coimmunoprecipitation experiments. The biological function of dopamine D4 receptor was investigated through in vivo experiments by intrathecal injection of shDRD4 to knockdown dopamine D4 receptor. In this study, we found that dapoxetine increased expression of 5-hydroxytryptamine and dopamine D4 receptor. We demonstrated that dapoxetine increased levels of 5-hydroxytryptamine, which promoted histone serotonylation (H3K4me3Q5ser) and transcription factor myeloid zinc-finger 1 complex binding on the dopamine D4 receptor promoter, upregulated the expression of dopamine D4 receptor and thus delayed ejaculation. In this study, we demonstrated that dapoxetine increased the levels of 5-hydroxytryptamine, which promoted histone serotonylation and myeloid zinc-finger 1 complex binding to the dopamine D4 receptor promoter and upregulated the expression of dopamine D4 receptor, thus delaying ejaculation. It is a novel mechanism that dapoxetine take effect of premature ejaculation treatment through upregulating the dopamine D4 receptor, which indicated that upregulated dopamine D4 receptor would enhance the dapoxetine effect in premature ejaculation treatment. This may lead to the development of novel therapeutic interventions for premature ejaculation.

Hypertrophic cardiomyopathy induces changes in the tryptophan-5-hydroxylase, serotonin transporter and serotonergic receptors expressions.

Cardiomyocytes have a biochemical machinery with the capacity to synthesize, utilize and reuptake serotonin. To determine whether hypertrophic cardiomyopathy (HCM) induces changes in the expression of tryptophan-5-hydroxylase (TPH) 1 and 2, serotonin transporter (SERT) and serotonergic receptors (SR). Cross-sectional study of five tissue blocks from hearts with HCM and five controls. Five sections of the left ventricular free wall (LVFW) and interventricular septum (IVS) were obtained from each block to determine the expression of TPH1 and TPH2, SERT and SRs by immunofluorescence with specific antibodies. Immunofluorescence was evaluated by WELCH t-test, with a level of significance of p < 0.05. LVFW and IVS of hearts with HCM showed an increase in the expression of TPH1 and TPH 2 and 5-HT2A and 5-HT2B receptors in comparison with controls (p < 0.01). The 5-HT4 receptor and SERT showed an increase in the IVS of hearts with HCM (p < 0.01). This study demonstrated an increased expression of TPH, SERT and SRs in cardiomyocytes from hearts with HCM in comparison with controls, which could be involved in the pathophysiology of HCM in humans.

Triptófano-5-hidroxilasa, transportador de serotonina y receptores serotoninérgicos en miocardiopatía dilatada.

Cardiomyocytes synthesize, utilize and reuptake serotonin, which is involved in the paracrine and autocrine modulation of heart activity and in the pathophysiology of some cardiovascular diseases. To determine the expression of tryptophan-5-hydroxylase (TPH) 1 and 2, serotonin transporter protein (SERT) and serotonergic receptors in hearts with dilated cardiomyopathy (DCM) compared to controls. A comparative study was performed in six tissue blocks of the left ventricular free wall (LVWL) and inter-ventricular septum from patients who died of DCM and six who died of no cardiovascular diseases (controls). Five slices from each block were obtained to determine the expression of TPH1 and TPH2, SERT and serotonergic receptors with antibodies specific for immunofluorescence. Immunofluorescence was analyzed by Student's t-test, accepting a significance level of p < 0.05. An increase in TPH1, TPH2, 5-HT2A and 5-HT2B receptors expression were observed in dilated structures compared to controls (p < 0.05). For dilated inter-ventricular septum, the 5-HT4 receptor increased its expression (p < 0.05), and SERT in PLVI compared to controls (p < 0.05). These results suggest that the increases observed in the expression of TPH, SERT, and serotonergic receptors in hearts with DCM compared to controls could play an important role in the pathophysiology of MCD in humans.

Fluvoxamine prompts the antitumor immune effect via inhibiting the PD-L1 expression on mice-burdened colon tumor.

A colon tumor, one of the digestive tract malignant tumors, is harmful to human health. A potential new treatment still deserves attention. The development of a new drug needs more resources, including time and expense. Therefore, the old drug with new targets has become a current research hotspot. Fluvoxamine, as an antidepressant, could play an effect on inhibiting 5-hydroxytryptamine reuptake. In the present research, the antitumor effects and possible mechanisms of fluvoxamine are validated. The results showed that fluvoxamine significantly suppressed the migration and proliferation of tumor cells, and increased the apoptosis in vitro. Additionally, fluvoxamine significantly delays tumor development, and prompts the apoptosis in tumor tissues of mice-burdened colon tumors in vivo. The tumor suppression might be related with that fluvoxamine inhibits the expression of phosphorylated signal transducer and activator of transcription 3, matrix metalloproteinase 2, and cleaved-caspase 3. Importantly, fluvoxamine significantly reduces the expression level of programmed cell death ligand1. This could be a possible reason that treatment with fluvoxamine drives the infiltration of T lymphocytes and M1-type macrophages in tumor tissues. Taken together, this research suggests that fluvoxamine might be a promising drug to treat colon cancer by inhibiting the proliferation and migration, inducing apoptosis, and even increasing the immune response of antitumor.

Influence of cerebral infarction on both bladder and urethral activities and changes after tramadol administration in rats.

We investigated the changes in bladder and urethral function after cerebral infarction (CI) and the influence of tramadol on these functions. Twenty-eight female Sprague Dawley rats were divided into normal and CI groups. In the awake condition, metabolic cage study and blood pressure were evaluated. Under urethane anesthesia, the intravenous effect of tramadol (0.01-1 mg/kg), which has both µ-opioid receptor stimulation and inhibition of norepinephrine and serotonin reuptake, on continuous cystometry, and simultaneous measurements of bladder and urethral perfusion pressure (UPP) were recorded. Infarcted lesions were examined by staining with triphenyltetrazolium chloride, a marker of mitochondrial enzyme activity. CI rats showed impaired sympathetic activity with Horner's syndrome and lower blood pressure. In metabolic cage study, urinary frequency during the dark phase was increased in CI rats. On bladder activity, in CI rats, the baseline pressure threshold for inducing bladder contractions was significantly lower (p &lt; 0.01), and the intercontraction interval was prolonged after tramadol administration. On urethral activity, the baseline UPP was significantly lower in CI rats than in normal rats and it did not change after tramadol administration. Residual urine rate was significantly increased in normal rats, but not in CI rats. CI rats showed brain infarction including the cortex and hypothalamus, which is a center of the autonomic nervous system. CI-induced ischemic brain damage results in impairment of both bladder and urethral functions, in addition to decreased sympathetic activity. Bladder overactivity after CI can be improved by tramadol; however, urethral activity cannot be improved by it.

Triiodothyronine Treatment reverses Depression-Like Behavior in a triple-transgenic animal model of Alzheimer's Disease.

Alzheimer disease's (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. The central nervous system is an important target of thyroid hormones (TH). An inverse association between serum triiodothyronine (T3) levels and the risk of AD symptoms and progression has been reported. We investigated the effects of T3 treatment on the depression-like behavior in male transgenic 3xTg-AD mice. Animals were divided into 2 groups treated with daily intraperitoneal injections of 20 ng/g of body weight (b.w.) L-T3 (T3 group) or saline (vehicle, control group). The experimental protocol lasted 21 days, and behavioral tests were conducted on days 18-20. At the end of the experiment, the TH profile and hippocampal gene expression were evaluated. The T3-treated group significantly increased serum T3 and decreased thyroxine (T4) levels. When compared to control hippocampal samples, the T3 group exhibited attenuated glycogen synthase kinase-3 (GSK3), metalloproteinase 10 (ADAM10), amyloid-beta precursor-protein (APP), serotonin transporter (SERT), 5HT1A receptor, monocarboxylate transporter 8 (MCT8) and bone morphogenetic protein 7 (BMP-7) gene expression, whereas augmented superoxide dismutase 2 (SOD2) and Hairless gene expression. T3-treated animals also displayed reduced immobility time in both the tail suspension and forced swim tests, and in the latter presented a higher latency time compared to the control group. Therefore, our findings suggest that in an AD mouse model, T3 supplementation promotes improvements in depression-like behavior, through the modulation of the serotonergic related genes involved in the transmission mediated by 5HT1A receptors and serotonin reuptake, and attenuated disease progression.

Platycladus orientalis seed extract as a potential triple reuptake MAO inhibitor rescue depression phenotype through restoring monoamine neurotransmitters

Ethnopharmacology relevancePlatycladus orientalis seeds are recorded in traditional Chinese medicine (TCM) formulations for modulation of mood and physical activity in “Shen Nong Ben Cao Jing” and “Compendium of Materia Medica” and so on. Recently, we identified its extracting components and looked for the potentials in treatment for depression by improving the function of monoamine neurotransmitters. Aim of the studyWe investigated the mechanism of action of the seed extracts of P. orientalis (S4) to rescue depressive behavior in a chronic, unpredicted, mild stress (CUMS)-induced model in rats. Materials and methodsWe used ultra-fast liquid chromatography coupled with triple quadrupole-time of flight tandem mass spectrometry to analyze the chemical constituents in S4. An assay platform in zebrafish and molecular docking were used to analyze if S4 regulated rest/wake behavior and predict the biological targets which correlated with monoamine neurotransmitters. Depressive-behavior tests (body weight, sucrose preference test, tail-suspension test, forced-swimming test) were carried in the CUMS model. After behavior tests and killing, rat brains were separated into the hippocampus, frontier cortex and dorsal raphe nucleus. The main monoamine neurotransmitters and their metabolite concentrations in these three brain regions were measured by rapid resolution liquid chromatography coupled with triple quadrupole tandem mass spectrometry. ResultsForty-one compounds were identified in S4, including fatty acids, terpenoids, amino acids, plant sterols and flavonoids. S4 could increase the total rest time and decrease the waking activity of zebrafish. S4 showed high correlation with adrenaline agonists, 5-hydroxytryptamine (5-HT) reuptake inhibitors and dopamine agonists. CUMS-group rats, compared with controls, had significantly decreased body weight and preference for sucrose water, whereas the immobility time in the tail-suspension test and forced-swimming test was increased. S4 could significantly rescue the increased levels of 5-HT, noradrenaline and dopamine in the prefrontal cortex and dorsal raphe nucleus. ConclusionsWe demonstrated that S4 was a potential inhibitor of MAO reuptake that could rescue depression in a CUMS-model rats by restoring monoamine neurotransmitters in different encephalic regions.

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice.

Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a “two-hit” stress mouse model. The “two-hit” stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the “two-hit” stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.

Resting-State fMRI in Predicting Response to Treatment With SSRIs in First-Episode, Drug-Naive Patients With Major Depressive Disorder.

ObjectiveFor major depressive disorder (MDD), there has been a lack of neuroimaging markers of efficacy of pharmacological treatment. In this study, we aimed to explore the neuroimaging mechanisms in patients with first-episode MDD and identify markers that predict the efficacy of 5-hydroxytryptamine reuptake inhibitors (SSRIs) with the use of resting-state brain imaging technology.MethodsA total of 101 patients with first-episode MDD and 53 normal controls were finally included in this study. Based on the reduction rate of the score of Hamilton Depression Rating Scale (HAMD-17) during the 2-week SSRI treatment, 31 patients were assigned into the unresponsive group and 32 were assigned into the responsive group. The brain function was compared between patients with MDD and normal controls, and the diagnostic value of brain function was analyzed. With brain regions showing differences between patients with MDD and normal controls as a mask, and the brain function between the responsive and unresponsive groups were compared. Correlations between brain function the HAMD-17 score reduction rate during the 2-week SSRI treatment were analyzed.ResultsCompared to normal controls, patients with MDD showed increased ReHo in the left parahippocampal gyrus and right parahippocampal gyrus, decreased ReHo in the right middle occipital gyrus, and decreased functional connectivity between the right and left parahippocampal gyri, right middle occipital gyrus and middle temporal gyrus. Receiver operator characteristic (ROC) curve analysis showed that the area under the curve (AUC) was 0.544 (95% CI: 0.445–0.644) for ReHo and 0.822 (95% CI: 0.734–0.909) for functional connectivity. Logistic regression pooling of the differences in ReHo mean time series with the functional connectivity mean time series was performed for the ROC curve analysis, which showed an AUC of 0.832 (95% CI: 0.752–0.911). Compared to the responsive group, the unresponsive group showed elevated ReHo in the right parahippocampal gyrus and lower functional connectivity in the middle temporal gyrus. We also found that the ReHo value was negatively correlated with the HAMD-17 score reduction after 2 weeks of SSRI treatment.ConclusionAltered resting-state brain function in some regions might be a neurobiological marker for the diagnosis of MDD, and ReHo values are expected to be predictors of patient response to treatment with SSRIs.Clinical Trial Registration[http://www.chictr.org.cn/], identifier [ChiCTR1900028722].

P.0751 Cognitive, psychological and pain dimensions in fibromyalgia patients responsive and resistant to treatment with serotonin and noradrenalin reuptake inhibitors

P.0751 Cognitive, psychological and pain dimensions in fibromyalgia patients responsive and resistant to treatment with serotonin and noradrenalin reuptake inhibitors

Environmentally realistic concentrations of cocaine in seawater disturbed neuroendrocrine parameters and energy status in the marine mussel Perna perna

Cocaine (COC) is a powerful illicit drug frequently detected in the aquatic environment. COC acts by inhibiting the reuptake of dopamine (DOPA) and 5-hydroxytryptamine (5-HT – serotonin) and causes endocrine disturbances in mammals. This study investigated similar effects from cocaine exposure in the marine mussel Perna perna, as well as neurotoxicity and energy imbalances. Mussels were exposed to COC (0.2 μg.L−1 and 2 μg.L−1) for periods of 48, 96, and 168 h. Acetylcholinesterase (AChE) was measured in adductor muscle tissue to determine neurotoxicity, and neurotransmitter levels (DOPA and 5-HT), monoamine oxidase (MAO) and cyclooxygenase (COX) activity, and energy status (mitrochondrial electron transport, MET, and total lipids, TLP) were evaluated in the mussels' gonads. COC decreased AChE activity in the mussels exposed to 0.2 μg.L−1 and 2 μg.L -1 after 168 h, and all concentrations of COC increased neurotransmitter levels. Increases in MET (0.2 μg.L -1, for all exposure periods) and TLP (0.2 μg.L 1 after 48 h, and 2 μg.L -1 after 96 h and 168 h) were also observed. No significant change was detected in MAO activity. COC also decreased COX activity in the mussels exposed to 0.2 μg.L -1 (48 h and 96 h) and 2 μg.L -1 (96 h). These results suggest that COC may compromise neurotransmitter levels and COX activity. Furthermore, the changes in MET and LPT suggest that COC affects the energy balance of the mussels, and could negatively affect physiological processes such as metabolism, hormone production, and embryonic development.