Serotonin syndrome controversies:A need for consensus

Serotonin syndrome(SS)is a drug-induced clinical syndrome resulting from increased serotonergic activity in the central nervous system.Although more than seven decades have passed since the first description of SS,it is still an enigma in terms of terminology,clinical features,etiology,pathophysiology,diagnostic criteria,and therapeutic measures.The majority of SS cases have previously been reported by toxicology or psychiatry centers,particularly in people with mental illness.However,serotonergic medications are used for a variety of conditions other than mental illness.Serotonergic properties have been discovered in several new drugs,including over-the-counter medications.These days,cases are reported in non-toxicology centers,such as perioperative settings,neurology clinics,cardiology settings,gynecology settings,and pediatric clinics.Overdoses or poisonings of serotonergic agents constituted the majority of the cases observed in toxicology or psychiatry centers.Overdose or poisoning of serotonergic drugs is uncommon in other clinical settings.Patients may develop SS at therapeutic dosages.Moreover,these patients may continue to use serotonergic medications even if they develop mild to moderate SS due to several reasons.Thus,the clinical presentation(onset,severity,and clinical features)in such instances may not exactly match what toxicologists or psychiatrists observe in their respective settings.They produce considerable diversity in many aspects of SS.However,other experts discount these new developments in SS.Since SS is a potentially lethal illness,consensus is required on several concerns related to SS.

Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.

Regulation of serotonin production by specific microbes from piglet gut

Background Serotonin is an important signaling molecule that regulates secretory and sensory functions in the gut.Gut microbiota has been demonstrated to affect serotonin synthesis in rodent models.However,how gut microbes regulate intestinal serotonin production in piglets remains vague.To investigate the relationship between microbiota and serotonin specifically in the colon,microbial composition and serotonin concentration were analyzed in ileum-cannulated piglets subjected to antibiotic infusion from the ileum when comparing with saline infusion.Microbes that correlated positively with serotonin production were isolated from piglet colon and were further used to investi-gate the regulation mechanisms on serotonin production in IPEC-J2 and a putative enterochromaffin cell line RIN-14B cells.Results Antibiotic infusion increased quantities of Lactobacillus amylovorus(LA)that positively correlated with increased serotonin concentrations in the colon,while no effects observed for Limosilactobacillus reuteri(LR).To understand how microbes regulate serotonin,representative strains of LA,LR,and Streptococcus alactolyticus(SA,enriched in feces from prior observation)were selected for cell culture studies.Compared to the control group,LA,LR and SA supernatants significantly up-regulated tryptophan hydroxylase 1(TPH1)expression and promoted serotonin production in IPEC-J2 cells,while in RIN-14B cells only LA exerted similar action.To investigate potential mechanisms mediated by microbe-derived molecules,microbial metabolites including lactate,acetate,glutamine,andγ-aminobutyric acid were selected for cell treatment based on computational and metabolite profiling in bacte-rial supernatant.Among these metabolites,acetate upregulated the expression of free fatty acid receptor 3 and TPH1 while downregulated indoleamine 2,3-dioxygenase 1.Similar effects were also recapitulated when treating the cells with AR420626,an agonist targeting free fatty acid receptor 3.Conclusions Overall,these results suggest that Lactobacillus amylovorus showed a positive correlation with sero-tonin production in the pig gut and exhibited a remarkable ability to regulate serotonin production in cell cultures.These findings provide evidence that microbial metabolites mediate the dialogue between microbes and host,which reveals a potential approach using microbial manipulation to regulate intestinal serotonin biosynthesis.

Serotonin enrichment of rice endosperm by metabolic engineering

In animals,serotonin is a neurotransmitter and mood regulator.In plants,serotonin functions in energy acquisition,tissue maintenance,delay of senescence,and response to biotic and abiotic stresses.In this study,we examined the effect of serotonin enrichment of rice endosperm on plant growth,endosperm development,and grain quality.To do so,TDCs and T5H were selected as targets for serotonin fortification.Overexpression of TDC1 or TDC3 increased serotonin accumulation relative to overexpression of T5H in rice grain.Transgenic lines of target genes driven by the Gt1 promoter showed better field performance than those driven by the Ubi promoter.Overexpression of T5H showed little effect on plant growth or grain physicochemical quality.In neuronal cell culture assays,serotonin induced neuroprotective action against apoptosis.Breeding of rice cultivars with high serotonin content may be beneficial for health and nutrition.

Differences of Plasma Levels of Tryptophan, Serotonin, 5-Hydroxyindole Acetic Acid, and Kynurenine between Healthy People and Patients of Major Monopolar Depression at Various Age and Gender

Background: It is not well analyzed whether there are differences in plasma levels of tryptophan (TRP) metabolites between healthy control people (HC) and patients of major monopolar depression (MMD). Methods: Ultra high-speed liquid chromatography/mass spectrometry has been used for the simultaneous determination of plasma levels of tryptophan metabolites in depressive patients. Results: There are no significant differences between plasma levels of TRP between HC and MMD. Plasma levels of TRP of HC are higher in young men, young women, old men, and old women in this order. Serotonin (5-HT) levels are higher in MMD than HC. Plasma levels of 5-HIAA of HC are also higher than those of patients of MMD. Plasma levels of kynurenine (KYN) of healthy old men and old women are higher than those of young men and old women. Plasma levels of KYN are higher in old women and young men of MMD than those of HC. Conclusion: Plasma levels of 5-HT are higher in patients of MMD than those of HC, which may suggest that use of drugs inhibiting the 5-HT transportation may increase plasma levels of 5-HT in MMD.

Association of serotonin transporter gene polymorphisms and major depressive disorder in Chinese Han population

BACKGROUND： Serotonin transporter （5-HTT） polymorphisms comprise 5-HTT gene-linked polymorphism region （5-HTTLPR） and variable number of tandem repeats （VNTR）. Studies have revealed an association between 5-HTT polymorphism and major depressive disorder, which suggests that the ＂S＂ allele of 5-HTTLPR and Stin2.9 of 5-HTTVNTR are associated with major depressive disorder. However, there are a number of studies that do not support the 5-HTT polymorphism effect in major depressive disorder. OBJECTIVE： To study the relationship between 5-HTT gene polymorphism and major depressive disorder in Chinese Han population. DESIGN, TIME AND SETTING： Case-controlled study of 5-HTT gene polymorphism. The experiment was performed at the Central Laboratory, Third Affiliated Hospital of Sun Yat-sen University, China from March 2005 to January 2006. PARTICIPANTS： A total of 99 depressive patients of Chinese Han nationality were recruited for this study. All patients met DSM-IV diagnostic criteria for major depressive disorder and had a total score of Hamilton Depression Scale （24 items） ≥21 points. In addition, 101 healthy subjects, matched for age and gender, served as the control group. METHODS： Venous blood was collected from all subjects. 5-HTT genotypes and alleles were determined by polymerase chain reaction. Consistent with the Hardy-Weinberg equilibrium, the association between 5-HTT gene polymorphism and major depressive disorder were analyzed by Chi-square test. MAIN OUTCOME MEASURES： 5-HTTLPR and 5-HTTVNTR genotypes and allele frequencies were measured. RESULTS： No significant differences in 5-HTTLPR genotypes and allele frequencies were determined between patients and controls （P 〉 0.05）. However, significant differences in 5-HTTVNTR genotypes and allele frequencies were detected （P 〈 0.01 ）. The Stin2.10 allele and 10/10 genotype associated with major depressive disorder （OR = 2.61,7.7, P 〈 0.05; analysis of dose-response relationships Х^2 = 12.35, P 〈 0.01）. CONCLUSION： Results from the present study revealed no association between 5-HTTLPR and major depressive disorder. However, a significant association between 5-HTTVNTR and major depressive disorder existed in a population of Chinese Han. The presence of Stin2.10 and 10/10 genotypes increased the risk for major depressive disorder in a dose-dependent manner.

Chronic serotonin syndrome:A retrospective study

BACKGROUND Serotonin syndrome(SS)is an underdiagnosed drug-induced clinical syndrome resulting from the excess intrasynaptic concentration of serotonin.Very limited information is available about chronic SS.AIM To evaluate the epidemiological,clinical,and other aspects of the insidious onset SS.METHODS We retrospectively evaluated 14 consecutive adult patients(>18 years)who had complaints for more than 6 wk at the time of consultation and met the Hunter criteria for SS.RESULTS The mean age was 41.1 years(range:21-61 years),with a male preponderance(64%).Although tremors were observed in all patients,this was a presenting complaint in only 43%of patients.Generalized body pain,insomnia,and restlessness were common presenting features(50%each).Other common clinical features were stiffness of the limbs(43%),diaphoresis(43%),gait disturbances(36%),bowel disturbances(36%),dizziness(29%),sexual dysfunctions(21%),incoordination(14%),and fatigue(14%)The mean duration of symptoms before the diagnosis of SS was 13.5±5.8 wk(range:6-24 wk).Amitriptyline was the most common drug(n=6,43%),followed by tramadol(n=5,36%)and sodium valproate(n=5,36%).All patients received cyproheptadine,a 5-hydroxytryptamine2A antagonist,as treatment and noted an excellent response CONCLUSION This study represents the largest study on chronic SS.We suggest that patients receiving serotonergic drugs should be physically examined for the presence of SS upon the development of new symptoms.

癫痫患儿血清serotonin、leptin的水平及临床意义

目的 探讨癫痫患儿血清中血清素(serotonin)、瘦素(leptin)的水平及其临床意义。方法 选取2019年4月至2021年4月咸宁市中心医院收治的102例癫痫患儿作为研究对象,随后根据癫痫发作频率分为频发组(A组,35例)、持续状态组(B组,27例)、非频发或持续状态组(C组,40例)。另选取同期在该院体检的102例健康儿童作为对照组。分别采用酶联免疫吸附法、放射免疫法检测儿童血清serotonin、leptin水平。采用Pearson相关分析探讨血清serotonin、leptin水平与C反应蛋白(CRP)、白细胞介素-2(IL-2)、肿瘤坏死因子-α(TNF-α)的关系,同时采用ROC曲线评价血清serotonin、leptin评估癫痫的临床价值。结果 癫痫各组及对照组儿童的血清serotonin、leptin的水平差异均有统计学意义(F值分别为76.710、79.640,P<0.05);进一步比较发现,serotonin水平:对照组>C组>B组>A组;leptin水平:A组>B组>C组>对照组,差异均有统计学意义(P<0.05)。癫痫各组及对照组儿童血清CRP、IL-2、TNF-α表达水平差异均有统计学意义(F值分别为813.920、560.602、507.530,P<0.05);进一步比较发现,A组>B组>C组>对照组,差异均有统计学意义(P<0.05)。相关性分析显示,癫痫患儿血清serotonin与CRP、IL-2、TNF-α均呈负相关(r值分别为-0.534、-0.528、-0.476,P<0.05),血清leptin与CRP、IL-2、TNF-α均呈正相关(r值分别为0.425、0.433、0.457,P<0.05)。血清serotonin、leptin评估癫痫的曲线下面积(AUC)及其95%CI分别为0.819(0.759~0.879)、0.835(0.765~0.897),二者联合检测的AUC(95%CI)为0.887(0.816~0.966)。结论 癫痫患儿血清中serotonin表达水平降低,leptin水平升高,且与癫痫发作频率及预后密切相关。Serotonin和leptin水平在辅助诊断癫痫上具有一定的价值。

Possible association of the 5-HTTLPR serotonin transporter promoter gene polymorphism with premature ejaculation in a Turkish population

We evaluated the genotypes of the serotonin transporter gene （5-HTT） in patients with premature ejaculation （PE） to determine the role of genetic factors in the etiopathogenesis of PE and possibly to identify the patient subgroups. A total of 70 PE patients and 70 controls were included in this study. All men were heterosexual, had no other disorders and were either married or in a stable relationship. PE was defined as ejaculation that occurred within 1 min of vaginal intromission. Genomic DNA from patients and controls was analyzed using polymerase chain reaction, and allelic variations of the promoter region of the serotonin transporter gene （5-HTTLPR） were determined. The 5-HTTLPR （serotonin transporter promoter gene） genotypes in PE patients vs. controls were distributed as follows： L/L 16% vs. 17%, L/S 30% vs. 53% and S/S 54% vs. 28%. We examined the haplotype analysis for three polymorphisms of the 5-HTTLPR gene： LL, LS and SS. The appropriateness of the allele frequencies in the 5-HTTLPR gene was analyzed by the Hardy-Weinberg equilibrium using the Z-test. The short （S） allele of the 5-HTTLPR gene was significantly more frequent in PE patients than in controls （P 〈 0.05）. We suggest that the 5-HTTLPR gene plays a role in the pathophysiology of all primary PE cases. Further studies are needed to evaluate the relationship between 5-HTTLPR gene polymorphism and patient subgroup （such as primary and secondary PE） responses to selective serotonin reuptake inhibitors as well as ethnic differences.

Serotonin样,Substance P样,Enkephalin样反应阳性神经元胞体在大鼠中缝核簇内的分布

本文用PAP法研究了Serotonin样,Substance P样,Leucine—Enkephalin样和Methionine—Enkephalin样反应阳性神经元胞体在大鼠中缝核簇内的分布。证明Serotonin存在于中缝苍白核、中缝隐核、中缝大核、中缝桥核、中央上核和中缝背核等处的某些神经元胞体内。以中、小细胞为主,在中缝大核内有少数大细胞。细胞形态为梭形、圆形、卵圆形以及多极细胞。Substance P样反应阳性胞体在上述中缝核内也被发现,其胞体的大小、形态和分布与serotonin样反应阳性胞体相似,但数目稍少。Leucine—Enkephalin样反应阳性胞体存在于中缝苍白核、中缝隐核、中缝大核、中缝桥核、中缝背核和中央上核内,但Methionine—Enkephalin样反应阳性细胞体仅在中缝苍白核和中缝隐核的吻侧部以及中缝大核内发现。后两者均以大,中型多极细胞为主。

Association between serotonin transporter gene polymorphisms and non-lesional temporal lobe epilepsy in a Chinese Han population

Serotonin （5-hydroxytryptamine, 5-HT） influences the cortical and subcortical excitatory/inhibitory balance and participates in the pathophysiological processes of epilepsy. The serotonin transporter （5-HTT） is the most important factor in serotonin inactivation. We tested whether 5-HTT polymorphisms are involved in the pathogenesis of epilepsy in Chinese Han population. We did not find a significant difference in the frequencies of genotypes and alleles in the 5-HTT gene-linked poLymorphic region （5-H-I-FLPR） in patients with non-lesional temporal lobe epilepsy and normal controls （P〉 0.05）. Frequencies of the 5-H1-1- intron 2 variable number tandem repeat （5-HTTVNTR） 12/12 genotype and allele 12 were higher in the patients with non-lesional temporal lobe epilepsy than normal controls （P 〈 0.01）. The odds ratio of affecting non-lesional temporal lobe epilepsy was 1.435 （95% Cl, 1.096 1.880） in patients carrying allele 12 （P 〈 0.05）. Although the 5-HTTLPR may not be a genetic locus of non-lesional temporal lobe epilepsy in Chinese Hart population, allele 12 in the 5-HTTVNTR may correlate with non-lesional temporal lobe epilepsy. The Stin2.12 allele and 12/12 genotype could be predisposing to non-lesional temporal lobe epilepsy.

Regulation of the serotonin transporter in the pathogenesis of irritable bowel syndrome

Serotonin(5-HT) and the serotonin transporter(SERT) have earned a tremendous amount of attention regarding the pathogenesis of irritable bowel syndrome(IBS). Considering that enteric 5-HT is responsible for the secretion, motility and perception of the bowel, the involvement of altered enteric 5-HT metabolism in the pathogenesis of IBS has been elucidated. Higher 5-HT availability is commonly associated with depressed SERT mR NA in patients with IBS compared with healthy controls. The expression difference of SERT between IBS patients and healthy controls might suggest that SERT plays an essential role in IBS pathogenesis, and SERT was expected to be a novel therapeutic target for IBS. Progress in this area has begun to illuminate the complex regulatory mechanisms of SERT in the etiology of IBS. In this article, current insights regarding the regulation of SERT in IBS are provided, including aspects of SERT gene polymorphisms, microR NAs, immunity and inflammation, gut microbiota, growth factors, among others. Potential SERT-directed therapies for IBS are also described. The potential regulators of SERT are of clinical importance and are important for better understanding IBS pathophysiology and therapeutic strategies.

补肾活血方对去势骨质疏松大鼠循环Serotonin表达的影响

目的探讨补肾活血方对去势大鼠循环5-羟色胺(Serotonin)表达水平的影响。方法 30只6月龄SD雌性大鼠去卵巢制作骨质疏松模型,另取10只行假手术,建立假手术组。3个月后,卵巢切除的大鼠随机分为三组,然后分别予补肾活血方(中药组),阿仑膦酸钠(西药组)和生理盐水(模型组)治疗,假手术组给予等量生理盐水。经过8周的治疗后处死大鼠,检测左侧股骨骨密度,ELISA检测血清Serotonin、核因子κB受体活化因子配体(RANKL)和骨转换指标P1NP、CTX水平。结果模型组骨密度低于假手术组(P<0.001);中药组和西药组全段股骨骨密度高于模型组(P<0.01和P<0.001)。中药组和西药组血清P1NP低于模型组(P均<0.001),而假手术组、中药组与西药组之间无统计学差异。中药组和西药组血清CTX低于模型组(P均<0.001),高于假手术组(P均<0.001)。中药组血清Serotonin水平低于西药组和模型组(P均<0.001),假手术组与中药组之间无统计学差异。中药组和西药组血清RANKL低于模型组(P均<0.001),假手术组、中药组与西药组之间无统计学差异。结论补肾活血方可能是通过降低去势大鼠循环Serotonin表达水平,进而抑制RANKL表达水平,从而提高去势大鼠骨密度。

Alterations in serotonin, transient receptor potential channels and protease-activated receptors in rats with irritable bowel syndrome attenuated by Shugan decoction

AIM:To determine the molecular mechanisms of Shugan decoction(SGD) in the regulation of colonic motility and visceral hyperalgesia(VHL) in irritable bowel syndrome(IBS).METHODS:The chemical compounds contained in SGD were measured by high-performance liquid chromatography.A rat model of IBS was induced by chronic water avoidance stress(WAS).The number of fecal pellets was counted after WAS and the pain pressure threshold was measured by colorectal distension.Morphological changes in colonic mucosa were detected by hematoxylin-eosin staining.The contents of tumor necrosis factor(TNF)-αin colonic tissue and calcitonin-gene-related peptide(CGRP)in serum were measured by ELISA.The protein expression of serotonin[5-hydroxytryptamide(5-HT)],serotonin transporter(SERT),chromogranin A(Cg A)and CGRP incolon tissue was measured by immunohistochemistry.RESULTS:SGD inhibited colonic motility dysfunction and VHL in rats with IBS.Blockers of transient receptor potential(TRP)vanilloid 1(TRPV1)(Ruthenium Red)and TRP ankyrin-1(TRPA1)(HC-030031)and activator of protease-activated receptor(PAR)4 increased the pain pressure threshold,whereas activators of PAR2and TRPV4 decreased the pain pressure threshold in rats with IBS.The effect of SGD on pain pressure threshold in these rats was abolished by activators of TRPV1(capsaicin),TRPV4(RN1747),TRPA1(Polygodial)and PAR2(AC55541).In addition,CGRP levels in serum and colonic tissue were both increased in these rats.TNF-αlevel in colonic tissue was also significantly upregulated.However,the levels of 5-HT,SERT and Cg A in colonic tissue were decreased.All these pathological changes in rats with IBS were attenuated by SGD.CONCLUSION:SGD alleviated VHL and attenuated colon motility in IBS,partly by regulating TRPV1,TRPV4,TRPA1,PAR2,5-HT,Cg A and SERT,and reducing CGRP and TNF-αlevel.

Effect of Lactobacillus rhamnosus GG supernatant on serotonin transporter expression in rats with post-infectious irritable bowel syndrome

AIM To evaluate the effect of Lactobacillus rhamnosus GG supernatant(LGG-s) on the expression of serotonin transporter(SERT) in rats with post-infectious irritable bowel syndrome(PI-IBS).METHODS Campylobacter jejuni 81-176(1010 CFU/m L) was used to induce intestinal infection to develop a PI-IBS model. After evaluation of the post-infectious phase by biochemical tests, Dn A agarose gel electrophoresis, abdominal withdrawal reflex(AWR) test, and the intestinal motility test, four PI-IBS groups received different concentrations of LGG-s for 4 wk. The treatments were maintained for 1.0, 2.0, 3.0 or 4.0 wk during the experiment, and the colons and brains were removed for later use each week. SERT m Rn A and protein levels were detected by real-time PCR and Western blot, respectively.RESULTS The levels of SERT m Rn A and protein in intestinal tissue were higher in rats treated with LGG-s than in control rats and PI-IBS rats gavaged with PBS during the whole study. Undiluted LGG-s up-regulated SERT m Rn A level by 2.67 times compared with the control group by week 2, and SERT m Rn A expression kept increasing later. Double-diluted LGG-s was similar to undiluted-LGG-s, resulting in high levels of SERT m Rn A. Triple-diluted LGG-s up-regulated SERT m Rn A expression level by 6.9-times compared with the control group, but SERT m Rn A expression decreased rapidly at the end of the second week. At the first week, SERT protein levels were basically comparable in rats treated with undiluted LGG-s, double-diluted LGG-s, and triplediluted LGG-s, which were higher than those in the control group and PBS-treated PI-IBS group. SERT protein levels in the intestine were also comparable in rats treated with undiluted LGG-s, double-diluted LGG-s, and triple-diluted LGG-s by the second and third weeks. SERT m Rn A and protein levels in the brain had no statistical difference in the groups during the experiment.CONCLUSION LGG-s can up-regulate SERT m Rn A and protein levels in intestinal tissue but has no influence in brain tissue in rats with PI-IBS.

Selective serotonin reuptake inhibitors and Alzheimer’s disease

Given the failure to develop disease-modifying therapies for Alzheimer’s disease(AD),strategies aiming at preventing or delaying the onset of the disease are being prioritized.While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on,a key determining factor may be the timing of depression onset in older adults.There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline.Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden,tau deposits and neurogenesis.In humans,studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors.Paroxetine,which has strong anticholinergic properties,was associated with increased mortality and mixed effects on amyloid and tau deposits in mice,as well as increased odds of developing AD in humans.Although most of the data regarding selective serotonin reuptake inhibitors is promising,findings should be interpreted cautiously because of notable methodological heterogeneity between studies.There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

Serotonin transporter and cholecystokinin in diarrhea-predominant irritable bowel syndrome: Associations with abdominal pain, visceral hypersensitivity and psychological performance

BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon movement and that serotonin transporter(SERT)is a transmembrane transport protein with high affinity for 5-hydroxytryptamine,which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity.We speculate that SERT and CCK might play a role in the pathogenesis of diarrheapredominant IBS(IBS-D)by affecting visceral sensitivity and the brain-gut axis.AIM To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain,visceral hypersensitivity and psychological performance.METHODS This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls.The severity of abdominal pain,visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls,the levels of SERT and CCK in plasma and colonic mucosa were evaluated,and the correlations between them were analyzed.RESULTS There were significant differences in the initial sensation threshold(31.00±8.41 mL vs 52.22±8.09 mL,P<0.001),defecating sensation threshold(51.75±13.57 mL vs 89.44±8.73 mL,P<0.001)and maximum tolerable threshold(97.25±23.64 mL vs 171.11±20.83 mL,P<0.001)between the two groups.IBS-D patients had more severe anxiety(7.78±2.62 vs 2.89±1.02,P<0.001)and depressive(6.38±2.43 vs 2.06±0.73,P<0.001)symptoms than healthy controls.Significant differences were also found in mucosal CCK(2.29±0.30 vs 1.66±0.17,P<0.001)and SERT(1.90±0.51 vs 3.03±0.23,P<0.001)between the two groups.There was a significant positive correlation between pain scores and mucosal CCK(r=0.96,0.93,0.94,P<0.001).Significant negative correlations between anxiety(r=-0.98;P<0.001),depression(r=-0.99;P<0.001),pain evaluation(r=-0.96,-0.93,-0.95,P<0.001)and mucosal SERT were observed.CONCLUSION IBS-D patients had psychosomatic disorders and visceral hypersensitivity.SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the braingut axis and affecting visceral sensitivity.This provides a new potential method for identifying a more specific and effective therapeutic target.

Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder： A Systematic Review and Meta-analysis

Attention deficit hyperactivity disorder （ADHD） is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have reported the association between the serotonin receptor family （5-HTR） gene polymorphisms and ADHD, but the results are still controversial. In this study, we conducted a meta-analysis of the association between 5-HTRIB, 5-HTR2A, and 5-HTR2C genetic variants and ADHD. The results showed that the 861G allele of 5-HTRIB SNP rs6296 could significantly increase the risk of ADHD （OR= 1.09, 95% CI： 1.01-1.18）; the 5-HTR2C gene rs518147 （OR=1.69, 95% CI： 1.38-2.07） and rs3813929 （OR = 1.57, 95% CI： 1.25-1.97） were all associated with the risk of ADHD. In addition, we also carried on a case- control study to explore the relevance between potential candidate genes 5-HTR1A, 5-HTRIE, 5-HTR3A and ADHD. The results indicated that 5-HTRIA rs6295 genotype （CC＋CG vs. GG OR=Z00, 95% CI： 1.23-3.27） and allele （OR=1.77, 95% CI： 1.16-2.72） models were statistically significantly different between case group and control group. This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD, and it also provides more evidence for the etiology of ADHD.

Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

Previous studies suggest that serotonin （5-HT） might interact with brain-derived neurotrophic factor （BDNF） during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry and in situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no significant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.