Contrasting effects of DOM and lisuride on impul-sive decision-making in delay discounting task / 中国药理学与毒理学杂志

OBJECTIVE The 5-HT2A receptor is the major target of classic hallucinogens.Both DOM(2,5-dimethoxy-4-methylamphetamine)and lisuride act at 5-HT2A receptors,and lisuride shares comparable affinity with DOM and acts as a partial agonist at 5-HT2A recep-tors.However,not like DOM,lisuride lacks hallucinogenic properties.Impulsive decision-making refers to the prefer-ence for an immediate small reinforcer(SR)over a delayed large reinforcer(LR).The current study aims to compare the effects of DOM and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs.METHODS Impulsive decision-making was evaluated in male Sprague-Dawley rats by the percent-age of choice for the LR in delay discounting task(DDT).Delay to the LR changed in an ascending order(0,4,8,16,and 32 s)across one session.RESULTS DOM(0.3 and 0.5 mg·kg-1)increased impulsive decision-making,and the effects of DOM(0.5 mg·kg-1)was blocked by the 5-HT2A receptor antagonist ketanserin(1.0 mg·kg-1)rather than the 5-HT2C receptor antagonist SB-242084(1.0 mg·kg-1).Contrarily,lisuride(0.1,0.3 and 0.5 mg·kg-1)decreased impulsive decision-making.The effects of lisu-ride(0.3 mg·kg-1)were not antagonized by ketanserin(1.0 mg·kg-1),selective 5-HT1A antagonist WAY-100635(1.0 mg·kg-1)or selective dopamine D4 receptor antagonist L-745870(1.0 mg·kg-1),but were attenuated by the selec-tive dopamine D2/D3 receptor antagonist tiapride(40 mg·kg-1).CONCLUSION DOM and lisuride have contrasting effects on impulsive decision-making via distinct recep-tors.DOM-induced increase of impulsivity is mediated by the 5-HT2A receptor,while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor.

Effect of Tongxie Yaofang on Expressions of Colon SERT and Liver 5-HT2AR Proteins in Rats with Ulcerative Colitis Model of Liver Stagnation and Spleen Deficiency / 中国实验方剂学杂志

Objective:To observe the effect of Tongxie Yaofang on the expressions of colon serotonin transporter （SERT）， liver 5-hydroxytryptamine_2A receptor （5-HT_2AR） protein， serum 5-HT and inflammatory factors in ulcerative colitis （UC） model rats of liver stagnation and spleen deficiency， in order to explore the basis of syndrome of liver stagnation and spleen deficiency and the intervention mechanism of Tongxie Yaofang. Method:Fifty male SD rats were randomly divided into blank control group， model group， high， medium and low-dose Tongxie Yaofang group （10，5，2.5 g·kg^-1）， and salazosulacil group （0.3 g·kg^-1）. The ulcerative colitis model of liver depression and spleen deficiency was established by 2，4，6-trinitrobenzene sulfonic acid （TNBS）/ethanol solution enema + restraint stress + diet loss. After successful modeling， the samples were collected after 21 days of drug intervention. Htoxylin eosin （HE） staining and oil red staining were used to observe the pathological changes of colon and liver in each group. Serum interleukin-6 （IL-6）， IL-9， 5-HT and superoxide dismutase （SOD） were detected by enzyme linked immunosorbent assay （ELISA）. Protein expressions of SERT in the colons and 5-HT_2AR in liver of rats were detected by Western blot. Result:Compared with the normal group， obvious ulcers were formed in the colon and lipid droplets in the liver increased in the model group， serum levels of IL-6， IL-9 and 5-HT in the model group increased， while the level of SOD decreased （<italic>P</italic><0.05）. The protein expression of SERT in colon decreased， whereas the protein expression of 5-HT_2AR in liver increased （<italic>P</italic><0.05）. Compare with model group， the pathological damage of colon was improved， and the formation of lipid droplets in liver was reduced in high， medium-dose Tongxie Yaofang groups and sulfasalazine group. The serum levels of IL-6， IL-9 and 5-HT decreased， while the level of SOD increased in Tongxie Yaofang group and sulfasalazine group （<italic>P</italic><0.05）. The protein expression of SERT in colon increased in high，low-dose Tongxie Yaofang groups and sulfasalazine group， and the protein expression of 5-HT_2AR in liver decreased in medium， low dose Tongxie Yaofang groups and sulfasalazine group （<italic>P</italic><0.05）. Conclusion:Tongxie Yaofang may reduce the content of 5-HT， and regulate the intestinal motility and sensory system by up-regulating the expression of SERT in the colon， inhibit the expressions of IL-6，IL-9 and other inflammatory factors， and play an anti-inflammatory role， reduce the content of 5-HT and the expression of 5-HT_2AR in the liver， increase the level of SOD， regulate emotion and lipid metabolism in the liver， and then exert the intervention effect on ulcerative colitis with liver depression and spleen deficiency on the whole.

The role of renal 5-hydroxytryptamine synthesis and degradation in hyperglycemia-induced kidney injury / 药学学报

Hyperglycemic kidney injury (HKI) is a common complication of diabetic patients. We examined the relationship between HKI and the abnormal expression of 5-hydroxytryptamine (5-HT) system induced by hyperglycemia in type 2 diabetes mellitus (T2DM). In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin. The mice were treated with the 5-HT2A receptor (5-HT2AR) antagonist sarpogrelate hydrochloride (SH) and 5-HT synthesis inhibitor carbidopa (CDP) (respectively or in combination). In cell culture experiments, human glomerular mesangial cells (HMC) were stimulated with D-glucose (D-Glu), and 5-HT2AR, 5-HT synthesis, and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor clorgyline. Periodic acid-Schiff (PAS) staining and Masson staining, immunohistochemistry and Western blot, fluorescent probe, and enzyme linked immunosorbent assay (ELISA) and enzyme reagent were respectively used to detect histopathology, protein expression, intracellular reactive oxygen species (ROS), and biochemical indexes. The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. The results showed that 5-HT2AR, 5-HT synthases, and MAO-A were expressed in glomerular basement membrane and kidney tubular epithelial cells of mouse kidney and HMC. The expression of these proteins was significantly up-regulated in T2DM mice or when HMC cells were exposed to high concentration of D-Glu. HKI, characterized by abnormal renal function, glomerular swelling, and glomerular basement membrane thickening and fibrosis, is closely associated with an increase in kidney 5-HT2AR, 5-HT synthesis, and 5-HT degradation. Among them, 5-HT2AR can mediate the expression of 5-HT synthases and MAO-A; MAO-A can catalyze the degradation of 5-HT to increase the production of mitochondrial ROS, leading to the phosphorylation of nuclear factor kappa B (NF-κB) with the production of inflammatory cytokines, and the up-regulation of matrix metalloproteinase-2 (MMP-2) and α-smooth muscle actin (α-SMA) with the production of collagens. SH and CDP can effectively treat HKI, and the combination of SH and CDP has a clear synergistic effect.

Relationship between fatigue caused by type 2 diabetes mellitus and 5-HT degradation in skeletal muscle / 药学学报

Fatigue is a common complication of type 2 diabetes mellitus (T2DM). We examined the relationship between T2DM fatigue and the skeletal muscle 5-hydroxytryptamine (5-HT) system. In animal experiments, a T2DM model was established in mice by feeding a high-fat diet with intraperitoneal injection of streptozotocin. The mice were treated with the 5-HT2A receptor antagonist sarpogrelate hydrochloride (SH) and the 5-HT synthesis inhibitor carbidopa (CDP) (separately and in combination). In cell culture experiments, C2C12 cells were stimulated with D-glucose, palmitic acid or 5-HT. 5-HT2AR, 5-HT synthesis and 5-HT degradation were inhibited by SH, CDP, or monoamine oxidase A (MAO-A) inhibitor. The animal experiments were in accordance with the regulations of the Animal Ethics Committee of China Pharmaceutical University. The results showed that 5-HT2AR, 5-HT synthase and MAO-A were expressed in mouse skeletal muscle and C2C12 cells. The expression of these proteins was significantly up-regulated in T2DM mice or when C2C12 cells were exposed to palmitic acid and D-glucose; palmitic acid was a stronger stimulant of their expression than D-glucose. Rotating rod experiments and biochemical index tests have shown that T2DM fatigue is associated with an increase in skeletal muscle 5-HT2AR, 5-HT synthesis and 5-HT degradation. 5-HT2AR mediates the expression of MAO-A and the synthesis of 5-HT, which indirectly regulates the degradation of 5-HT. MAO-A regulates cell inflammation, mitochondrial ROS production and membrane potential depolarization by mediating 5-HT degradation. MAO-A also inhibits the expression of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1), carnitine palmitoyltransferase-1 (CPT1) and ATP synthase-6 (ATP6), thus inhibiting mitochondrial functions such as fatty acid β oxidation and ATP synthesis. SH and CDP can effectively treat T2DM fatigue, and can also reduce blood glucose and blood lipid, and the combination of SH and CDP has a clear synergistic effect.

Protective Effects of 5-HT1A Receptor Inhibition and 5-HT2A Receptor Stimulation Against Streptozotocin-Induced Apoptosis in the Hippocampus

@#Introduction: Intracerebroventricular administration of streptozotocin (icv-STZ) induced apoptosis changes in neurons similar to Alzheimer's disease. The serotonergic system via its receptor involved in survival of neurons. The present study examined the ability of selective 5-HT1A receptor antagonist (NAD-299) and 5-HT2A receptor agonist (TCB-2) to attenuate the apoptosis caused by the icv-STZ in the rat. Methods: The icv-STZ (3 mg/kg, 10 μL, twice) induced neuronal loss in the hippocampus of adult male rats. Animals were divided into naive control, sham-operated, STZ+saline (1 μL, icv), STZ+NAD-299 (5 μg/μL, icv), STZ+TCB-2 (5 μg/μL, icv), and STZ+NAD-299+TCB-2 (5 μg/μL of any agent, icv) groups. Following the 35 days’ treatment period, neuronal apoptosis was detected using the Tunnel. Cells with morphological features of apoptotic cell were contended by microscopy. Results: TCB-2 and NAD-299 administration decreased number of apoptotic neurons in the treatment group compared with the STZ group. Combined treatment of STZ rat with NAD+TCB more decreased number of apoptotic cells in compare to TCB-2 or NAD-299 treated STZ groups. Conclusion: Treatment with 5-HT1A receptor antagonist or 5-HT2A receptor agonist diminished apoptosis. The beneficial effect of 5HT1A receptor inhibition was potentiated with activation of 5-HT2A receptor in prevention of apoptosis in hippocampus.

An experiment research on the expression of 5-HT 2A receptor in the prefrontal cortex of traumatic brain injury-induced coma rats following median nerve electrical stimulation / 中国康复医学杂志

Objective:To investigate the expression of 5-HT 2A receptor in the prefrontal cortex of traumatic brain injuryinduced coma rats after median nerve electrical stimulation.Method:A total of 72 SD rats (weighing 250-300g) were randomly divided into 4 groups:a stimulationgroup,an antagonist group,a sham-stimulation group and a control group.This traumatic brain injury model was established by a weight-drop head injury,and we evaluated the change of behavior through the six classical levels of consciousness.The animals were sacrificed and their brain tissues were removed at 6,12,and 24 hours after injury.5-HT 2A protein expression was examined by immunohistochemistry.Result:Thirteen rats exhibited righting reflex in the stimulation group.In the antagonist group,9 rats exhibited righting reflex.5 rats in the sham-stimulation group had the same response.The mean rank of consciousness degree were degree 9.50 in the control group,degree 52.75 in the sham-stimulation group,degree 37.61 in the stimulation group,degree 46.14 in the antagonist group.Comparison among groups presented an increasing consciousness degree:control group＜stimulation group＜antagonist group＜sham-stimulation group(P＜0.01).Resuits from immunohistochemistry showed that significant differences in the 5-HT 2A expression among the four groups (sham-stimulation＜control＜antagonist＜stimulation))(P＜0.05),and a within-group comparison showed that the 5-HT 2A expression level was as follows:6 hours＜24 hours ＜12 hours(P＜0.05).Conclusion:Median nerve electrical stimulation might modulate wakefulness by promoting the 5-HT 2A expression via orexin-A in the prefrontal cortex of rats with traumatic brain injury-induced coma.

Effects of intraperitoneal injection of 5-HT2A receptor antagonist MDL11939 on acute and chronic pain in mice / 中国药理学通报

Aim To investigate the effects and signifi-cance of 5-HT2A receptor antagonist MDL1 1 939 on a-mice.Methods Kunming male mice were suffered a-cute acetic acid visceral pain,acute incision pain and CCI neuropathic pain.After each animal model was es-tablished,MDL1 1 939 was injected intraperitoneally. The writhing reaction was used to assess acute acetic acid visceral pain,while the thermal withdrawal laten-cy (TWL)was used to evaluate the acute incision pain and CCI neuropathic pain.Results Compared with the control group,MDL1 1 939 (0.25,0.5,1 .0 mg· kg -1 ,i.p.)relieved acetic acid visceral pain signifi-cantly in a dose-dependent manner in mice,as re-vealed by the significant reduction of the number of twisting.In acute incision pain and CCI neuropathic pain,MDL1 1 939 (0.5 mg·kg -1 ,i.p.)significantly increased TWL level.Conclusion 5-HT2A receptor antagonist MDL1 1 939 has analgesic effects on visceral pain,acute pain and neuropathic pain,which might be a novel therapeutic target to treat different pain in clini-cal situations.

Pimavanserin:a New Drug for the Treatment of Psychosis Associated with Parkinson' s Disease / 中国药师

Pimavanserin is a selective 5-HT2A receptor inverse agonist approved by FDA on April 29, 2016, and it is the first drug for the treatment of hallucinations and delusions associated with Parkinson' s disease. Pimavanserin is with high safety, good toleration and promising clinical efficiency, which is a timely option to resolve the drug shortage in clinic treatment. This paper summarized its pharmacodynamics, pharmacokinetics, clinical studies, adverse reactions and drug interactions.

Advances in synthesis of pimavanserin / 国际药学研究杂志

Pimavanserin(Nuplazid) is a drug of selective targeting 5-HT2A receptor,developed by Acadia Pharmaceuticals. In April 29,2016,it was approved by FDA for the treatment of Parkinson′s disease(PD)patients experiencing mental symptoms such as hallucinations and delusions. In this paper,we summarize the synthetic methods of pimavanserin published in literature in re?cent years and their advantages and disadvantages.

Aripiprazole in patients with bipolar disorder D2 receptor and 5 -HT1A receptor partial agonists and analysis of 5-HT2A receptor antagonism / 中国基层医药

Objective To explore the efficacy of aripiprazole in patients with bipolar disorder D2 receptor and 5 -HT1A receptor partial agonists and analyze 5 -HT2A receptor antagonism.Methods From January 2013 to January 2015,113 patients came to our hospital for treatment of bipolar disorder,in accordance with the order of admission,were divide into aripiprazole group (47 cases)and control group (66 cases).The control group was given venlafaxine,aripiprazole group was given aripiprazole treatment on the basis of the control group.SDS,BRMS score and therapeutic effect were compared between the two groups before and after treatment.Results The SDS,BRMS scores were decreased after treatment in the two groups,compared with before treatment,the differences were statisti-cally significant (t =31.3587,36.1207;all P <0.05 );and the aripiprazole group decreased more significantly than the control group,the SDS,BRMS scores of the two groups after treatment had statistically significant differences [SDS (31.8 ±4.3)points vs (28.7 ±3.6)points,BRMS (6.5 ±0.2)points vs (5.5 ±0.2)points,t =4.110 7,26.197 0, all P <0.05 ].The total effective rate of the aripiprazole group was 97.9%,which was significantly higher than 89.4% of the control group (u =3.365 9,P =0.000 8).The incidence rate of adverse reactions such as nausea, vomiting,drowsiness,anxiety and heart rate in the aripiprazole group was significantly lower than the control group (all P <0.05 ).Conclusion Aripiprazole for bipolar disorder patients with D2 receptor and 5 -HT1A receptor has partial agonism,of 5 -HT2A receptor with role constraints,can effectively improve the effect of treatment of patients,reduce the incidence of adverse reactions.

Advances in synthesis of pimavanserin / 国际药学研究杂志

Pimavanserin(Nuplazid) is a drug of selective targeting 5-HT2A receptor, developed by Acadia Pharmaceuticals. In April 29, 2016, it was approved by FDA for the treatment of Parkinson’s disease (PD) patients experiencing mental symptoms such as hallucinations and delusions. In this paper, we summarize the synthetic methods of pimavanserin published in literature in recent years and their advantages and disadvantages.

Facilitation of serotonin-induced contraction of rat mesenteric artery by ketamine

Ketamine is an anesthetic with hypertensive effects, which make it useful for patients at risk of shock. However, previous ex vivo studies reported vasodilatory actions of ketamine in isolated arteries. In this study, we reexamined the effects of ketamine on arterial tones in the presence and absence of physiological concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) by measuring the isometric tension of endothelium-denuded rat mesenteric arterial rings. Ketamine little affected the resting tone of control mesenteric arterial rings, but, in the presence of 5-HT (100~200 nM), ketamine (10~100 µM) markedly contracted the arterial rings. Ketamine did not contract arterial rings in the presence of NE (10 nM), indicating that the vasoconstrictive action of ketamine is 5-HT-dependent. The concentration-response curves (CRCs) of 5-HT were clearly shifted to the left in the presence of ketamine (30 µM), whereas the CRCs of NE were little affected by ketamine. The left shift of the 5-HT CRCs caused by ketamine was reversed with ketanserin, a competitive 5-HT(2A) receptor inhibitor, indicating that ketamine facilitated the activation of 5-HT(2A) receptors. Anpirtoline and BW723C86, selective agonists of 5-HT(1B) and 5-HT(2B) receptors, respectively, did not contract arterial rings in the absence or presence of ketamine. These results indicate that ketamine specifically enhances 5-HT(2A) receptor-mediated vasoconstriction and that it is vasoconstrictive in a clinical setting. The facilitative action of ketamine on 5-HT(2A) receptors should be considered in ketamine-induced hypertension as well as in the pathogenesis of diseases such as schizophrenia, wherein experimental animal models are frequently generated using ketamine.

Effects of Kaixin Powder on Expression of 5-HT Receptor in Hippocampus of Depressed Rats Induced by CUMS / 中草药·英文版

Objective: To observe the influence of Kaixin Powder on ethology, content of 5-HT in the hippocampus, expression of mRNA, and protein in 5-HT1A and 5-HT2A receptors in the hippocampus of depressed rats induced by chronic unpredictable mild stress (CUMS). Methods: Twenty-four male Wistar rats were randomly divided into blank, model, Trazodone, and Kaixin Powder groups, six rats in each group. In addition to the blank control group, other groups were established the depression model induced by CUMS combined with isolated feeding. At the same time, Trazodone group and Kaixin Powder group were treated with corresponding drugs for 3 weeks. After 3 weeks of administration, the rats were sacrificed, and a series of indexes were measured such as the contents of 5-HT, mRNA expression levels of 5-HT1A and 5-HT2A receptors, protein expression levels of 5-HT1A and 5-HT2A receptors, and so on. Results: A series of indexes in the model group were decreased significantly such as the body weight growth, the sugar water intake, the score of Open Field Test, the content of 5-HT in the hippocampus, expression of mRNA, and protein in 5-HT1A receptor, while the expression of mRNA and protein in 5-HT2A receptor were increased significantly. Compared with the model group, the indexes were ameliorated in Trazodone and Kaixin Powder groups. Kaixin Powder is better than Trazodone in decreasing the level of protein in 5-HT2A receptor. Conclusion: The result indicated that the depression performance of depressed rats induced by CUMS can be ameliorated by Kaixin Powder, and the mechanism maybe concerned with increasing the contents of 5-HT, exciting 5-HT1A receptor, and antagonising 5-HT2A receptor.

5-Hydroxytryptamine (serotonin) 2A receptor gene polymorphism is associated with schizophrenia.

Background & objectives: Schizophrenia, the debilitating neuropsychiatric disorder, is known to be heritable, involving complex genetic mechanisms. Several chromosomal regions associated with schizophrenia have been identified during the past; putative gene (s) in question, to be called the global signature for the pathophysiology of the disease, however, seems to evade us. The results obtained from the several population-wise association-non association studies have been diverse. we therefore, undertook the present study on Tamil speaking population in south India to examine the association between the single nucleotide polymorphisms (SNPs) at the serotonin receptor gene (5HT2A) and the occurrence of the disease. Methods: Blood samples collected from 266 cases and 272 controls were subjected to genotyping (PCR amplification of candidate SNPs, RFLP and sequencing). The data on the SNPs were subjected to statistical analysis for assessing the gene frequencies in both the cases and the controls. Results: The study revealed significant association between the genotypic frequencies of the serotonin receptor polymorphism and schizophrenia. SNP analysis revealed that the frequencies of GG (30%, rs6311) and CC genotypes (32%, rs6313), were higher in patients (P<0.05) than in controls. The study also showed presence of G and C alleles in patients. significant levels of linkage disequilibrium (LD) were found to exist between the genotype frequencies of rs6311 and rs6313. Interpretation & conclusions: This study indicated an association between the SNPs (rs6311 and rs6313) of the serotonin receptor 5HT2A and schizophrenia. HapMap analysis revealed that in its genotype distribution, the Tamil speaking population was different from several other populations across the world, signifying the importance of such ethnicity-based studies to improve our understanding of this complex disease.

Correlation of serotonin 2A receptor and adenylate cyclase single gene polymorphisms and bipolar disorder / 中华行为医学与脑科学杂志

Objective To explore whether there is association between the polymorphisms of serotonin 2A receptor(5-HT2A) rs6311,rs6305 and adenylate cyclase rs2230739 with episode of bipolar disorder.Methods A case-control association study was done in this study,152 bipolar disorder patients (patients group),and 187 ageand gender-matched controls (control group) were recruited.Ligase detection reaction(LDR) was used to detect the distributive frequency of rs6311,rs6305 and rs2230739 of 152 bipolar disorder patients and 187 normal people.Results The 5-HT2A receptor rs6311 genotypes and alleles frequency distribution between patients group(11,12,22 genotypes:21％,61％,18％ ; 1,2 alleles:51％,49％) and control group(11,12,22 genotypes:44％,45％,11％ ; 1,2 alleles:66％,34％) showed statistically significance (P＜0.01).There were no differences of 5-HT2A receptor rs6305 genotypes and alleles between patients group and control group.The frequency of rs2230739 genotypes and alleles distribution between patients group (11,12,22 genotypes: 20％,43％,37％ ; 1,2 alleles: 42％,58％) and control group(11,12,22 genotypes: 17％,48％,35％ ; 1,2 alleles: 41％,59％) showed no significant difference(P=0.661,P=0.846).Conclusion The 5-HT2A receptor rs6311 polymorphism may be responsible for an increase in susceptibility to bipolar disorder,indicating that it maybe an marker to bipolar disorder.

Expression of 5-HT2A receptor in brainstem affects the occurrence of central sleep apnea in Sprague-Dawley rat / 实用医学杂志

Objective To investigate the correlationship of 5-HT2A receptor expression in the brainstem and sleep apnea in Sprague-Dawley (SD)rat. Method PSG monitoring for sleep and sleep apneas scoring was performed in freely moving SD rats. The level of 5-HT2A protein in rat brainstem was detected by Western blot and the relationship of 5-HT2A level with sleep apneas was analyzed. Results Two types sleep apnea model were obtained in rats, one was post-sigh sleep apnea (PS) and the other was spontaneous apnea (SP). The sleep apnea index was negatively correlated with the amount of 5-HT2A receptor level in brainstem (r=0.672,P 0.05). Conclusion The expression of 5-HT2A receptor in brainstem was negatively correlated with the severity of post-sigh sleep apnea. This association implies that 5-HT 2A receptor plays a critical role in the respiratory network and is closely correlated with the occurrence of central sleep apneas.

Effect of ningdong granule on 5-hydroxytryptamine metabolism and 5-HT 2AR of tourette’s syndrome rat models / 国际中医中药杂志

Objective To investigate the effect of Ningdong granule on 5-hydroxytryptamine metabolism and 5-HT2AR of Tourette’s Syndrome(TS) rat models. Methods 32 SD rats were divided into 4 groups randomly, the control group, the model (Apo) group, the low dosage NDG (NGL) group, and the high dosage (NGH) group. TS rat models were induced by intraperitoneal injection (i.p.) with Apo (2 mg/kg) in the experimental groups last 4 weeks. Rats in the control group were injected with normal saline (0.9%) (3 ml/kg, i.p.). Then, the rats were treated by intragastric administration (i.g.) with ND granular at 1.8g/(kg?d)in NGL group, with ND granular at 3.6 g/(kg?d)in NGH group, with distilled water at equal Volume in Control group and Apo group respectively for 12 successive weeks. Analysis the striatum 5-HT2AR protein expression by Immunohistochemical method;Determination of the content of 5-HT and 5-HIAA in striatum by Enzyme linked immunosorbent assay (ELISA). Results The level of 5-HT and 5-HT2AR protein expression in the model group [(1.98±0.14)ng/ml and(143.10±8.01)], compared with the control group[(1.78±0.10)ng/ml and(127.43±6.72)], was up-regulated (P<0.01 or 0.05). The levels of 5-HT and 5-HT2AR protein expression in NGH group[(2.20±0.14)ng/ml and(166.33±9.21)ng/ml] were further up-regulated, and the levels of 5-HIAA in NDH group [(0.58±0.08) ng/ml] became lower, compared with the control group(P<0.01 or 0.05). Conclusion Activity of 5-HT system enhanced in Apo-induced TS rat model. However, the enhanced activity may still be relatively insufficient. The mechanism of ND granulear treating TS was associated with depression of the 5-HT metabolism, up-regulation expression of 5-HT2AR, and improving the activity insufficient of 5-HT system.

Effects of nonylphenol on 5-hydroxytryptamine and its 2A receptor in rats / 第二军医大学学报

Objective To observe the effect of nonylphenol (NP) on plasma and urine 5-hydroxytryptamine (5-HT) levels and expression of 5-HT and of 5-HT2A receptor in the platelets of rats, so as to explore the toxic mechanisms of NP on 5-HT and 5-HT2A receptor.

Behavioral Patterns and Expression of Genes Coding Serotonin Receptors in Rats with Ultrasound Induced Depression.

Aims: The aim of our study was to investigate the effects of continuous action of ultrasonic waves of variable frequencies on behavior of rats in "classical" tests used to reveal depression-like behavior, to evaluate the influence of different psychotropic drugs on rates of these tests and to analyze expression of several genes involved in pathogenesis of depression. Study Design: Rats in individual cages were exposed to ultrasonic irradiation for 21 days. Place and Duration of Study: V.P. Serbsky National Recearh Center For Social and Forensic Psychiatry, Department of Basic and Applied Neurobiology, Moscow, Russian Federation, between November 2012 and January 2013. Methodology: 48male non-pedigree albino rats were divided into 5 groups: nonultrasound- saline, ultrasound-saline, ultrasound-fluoxetine, ultrasound-bupropion and ultrasound-tianeptine. After 21 days of irradiation social interaction test, forced swimming test and sucrose preference test (anhedonia test) were conducted. Than rats were decapitated and prefrontal cortex were taken for RT-qPCR gene expression analysis of 5-HT1A, 5-HT2A, 5HT1B, 5HT2B receptors and SERT. Results: Depression-like behavior manifests itself in reduced social activity in social interaction test, increased immobility in forced swimming test and lower sucrose consumption in anhedonia test. The administrated antidepressants demonstrated their effectiveness, except for bupropion in the social interaction test. RT-qPCR gene expression analysis showed reduced expression of 5HT2A receptor gene and increased expression of SERT gene in the prefrontal cortex of rats stressed with ultrasonic radiation. Conclusion: The obtained data allow to conclude that further investigations with lager number of animals, extended tests battery may allow to claim that this model meets the main requirements set to animal models (face, predictive and construct validity) and can be used in studies of depression-like disorders caused by a situation of informational uncertainty and in pre-clinical development of new antidepressants.

Serotonin contracts the rat mesenteric artery by inhibiting 4-aminopyridine-sensitive Kv channels via the 5-HT2A receptor and Src tyrosine kinase

Serotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive voltage-gated K+ (Kv) channels determine the resting membrane potential of arterial smooth muscle cells and that the Kv channels are inhibited by 5-HT, which depolarizes the membranes. Therefore, we hypothesized that 5-HT contracts arteries by inhibiting Kv channels. Here we studied 5-HT signaling and the detailed role of Kv currents in rat mesenteric arteries using patch-clamp and isometric tension measurements. Our data showed that inhibiting 4-AP-sensitive Kv channels contracted arterial rings, whereas inhibiting Ca2+-activated K+, inward rectifier K+ and ATP-sensitive K+ channels had little effect on arterial contraction, indicating a central role of Kv channels in the regulation of resting arterial tone. 5-HT-induced arterial contraction decreased significantly in the presence of high KCl or the voltage-gated Ca2+ channel (VGCC) inhibitor nifedipine, indicating that membrane depolarization and the consequent activation of VGCCs mediate the 5-HT-induced vasoconstriction. The effects of 5-HT on Kv currents and arterial contraction were markedly prevented by the 5-HT2A receptor antagonists ketanserin and spiperone. Consistently, alpha-methyl 5-HT, a 5-HT2 receptor agonist, mimicked the 5-HT action on Kv channels. Pretreatment with a Src tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, prevented both the 5-HT-mediated vasoconstriction and Kv current inhibition. Our data suggest that 4-AP-sensitive Kv channels are the primary regulator of the resting tone in rat mesenteric arteries. 5-HT constricts the arteries by inhibiting Kv channels via the 5-HT2A receptor and Src tyrosine kinase pathway.