Support vector classification for SAR of 5-HT3 receptor antagonists

In this work, support vector classification （SVC） algorithm was used to build structure-activity relationship （SAR） model of the 5-hydroxytryptamine type 3 （5-HT3 ） receptor antagonists with 26 compounds. In a benchmark test, SVC was compared with several techniques of machine learning currently used in the field. The prediction performance of the model was discussed on the basis of the leave-one-out cross-validation. The results show that the accuracy of prediction of SVC model was higher than those of back propagation artificial neural network （BP ANN）, K-nearest neighbor （KNN） and Fisher methods.

Inhibition of 5-HT_3 Receptors-activated Currents by Cannabinoids in Rat Trigeminal Ganglion Neurons

This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.

Effects of Activation and Blockade of Serotonin 5-HT1A Receptors on the Immune Response in Rats Selected for Different Levels of Aggressiveness

The present study examines the effects of serotonin (5-HT) 1A receptor ligands on humoral im-mune response in two rat lines selected for over 75 generations for the enhancement or elimination of aggression. Activation of presynaptic 5-HT1A receptors with a low dose of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.1 mg/kg) or the blockade of postsynaptic 5-HT1A receptors with the antagonist WAY-100635 (1.0 mg/kg) did not affect the numbers of IgM-antibody forming cells (IgM-AFC) in the spleen of highly aggressive rats, which were characterized by higher immune responsiveness compared to nonaggressive line. On the other hand, the same doses of 8-OH-DPAT and WAY-100635, as well as a higher dose of 8-OH-DPAT (1.0 mg/kg), which is known to activate postsynaptic 5-HT1A receptors, produce immunostimulation in nonaggressive rats. However, only the highest dose of 8-OH-DPAT (5.0 mg/kg) was able to cause immunosuppression in nonaggressive rats that was mainly dependent on stimulation of postsynaptic 5-HT1A receptors. In contrast to nonaggressive rats, the dose of 1.0 mg/kg 8-OH-DPAT was sufficient to produce a decrease in the numbers of IgM-AFC in highly aggressive rats. Thus, pharmacological activation of pre- and postsynaptic 5-HT1A receptors, as well as the blockade of postsynaptic 5-HT1A receptors, produced different effects on the immune response in two lines of rats selected for high level of aggression or its absence. These data may have implications for more efficient treatments of a number of mental disorders associated with abnormal aggression.

戊己丸不同配伍方对结肠平滑肌细胞5-HT3,4受体及下游信号传导通路主要元件的影响

目的:观察戊己丸不同配伍方对平滑肌细胞5-羟色胺3,4受体及其下游信号通路的影响。方法:采用Bitar的方法分离培养大鼠结肠平滑肌细胞,α-actin免疫组化鉴定。应用免疫荧光法和钙离子探针检测5-羟色胺3,4受体表达及Ca2+浓度;应用ELISA试剂盒检测cAMP,PKA的浓度。结果:1号方和2号方对大鼠结肠平滑肌细胞5-羟色胺3,4受体的表达及Ca2+浓度均具有抑制作用(P<0.05);可显著下调平滑肌细胞的cAMP和PKA水平(P<0.05);2号方作用效果优于1号方。结论:戊己丸可抑制5-羟色胺3,4受体表达及下调Ca2+,cAMP,PKA水平。

Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome:A multicenter retrospective study

BACKGROUND Single-nucleotide polymorphisms(SNPs)of the serotonin type 3 receptor subunit(HTR3)genes have been associated with psychosomatic symptoms,but it is not clear whether these associations exist in irritable bowel syndrome(IBS).AIM To assess the association of HTR3 polymorphisms with depressive,anxiety,and somatization symptoms in individuals with IBS.METHODS In this retrospective study,623 participants with IBS were recruited from five specialty centers in Germany,Sweden,the United States,the United Kingdom,and Ireland.Depressive,anxiety,and somatization symptoms and sociodemographic characteristics were collected.Four functional SNPs—HTR3A c.-42C>T,HTR3B c.386A>C,HTR3C c.489C>A,and HTR3E c.*76G>A—were genotyped and analyzed using the dominant and recessive models.We also performed separate analyses for sex and IBS subtypes.SNP scores were calculated as the number of minor alleles of the SNPs above.The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays.RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model(F_(depressive)=7.475,P_(depressive)=0.006;F_(anxiety)=6.535,P_(anxiety)=0.011).A higher SNP score(range 0-6)was linked to a worsened depressive symptoms score(F=7.710,P-linear trend=0.006)in IBS.The potential relevance of the HTR3C SNP was corroborated,showing changes in the expression level of 5-HT3AC variant receptors.CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS.The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

1-(N-(2-(2-Methoxyphenylthio)benzyl)-N-methylamino-3-aryloxypropan-2-ols:Synthesis and evaluation for dual 5-HT_(1A)/SSRI activities

A series of 1-（N-（2-（2-methoxyphenylthio）benzyl）-N-methylamino-3-aryloxypropan-2-ols derivatives were designed and synthesized based on 5-HT1A/SSRI drugs design strategies. The synthesized compounds were evaluated for their dual 5-HT1A/ 5-HTT activities. 2007 Ai Jun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Targeted to medication-induced dyskinesia and tardive dyskinesia:A role of 5-HT_(1A) receptor

Objective To outline the recent progress in drug discovery for medication-induced dyskinesia(Parkinson disease,PD)and tardive diskinesia(schizophrenia)with emphasizing the role of 5-HT1A receptor.Methods Development of extrapyramidal syndrome(EPS)followed either chronic L-DOPA administration in PD(L-DOPA-induced dyskinesia,LID)or antipsychotic treatment in schizophrenia(Tardive dyskinesia,TD)remains a challenge in the clinical practice and drug discovery.In addition to the abnormal dopamine activity in the nigrostrial area that contributes to the LID or TD,recent information indicates that 5-HT1A receptor also plays an important role which is merging as promising target in treatment of LID or TD.Results l-Stepholidine(l-SPD),isolated from the Chinese herb Stephania,is known as a dual dopamine receptor agent(D1 receptor agonistic and D2 antagonistic activity).In addition,we further demonstrated that l-SPD binds to 5-HT1A receptor and exhibits a partial agonistic activity.In LID rat model,l-SPD not only attenuated the development of L-DOPA-induced dyskinesia(LID),but also relived the established LID.The effect of l-SPD on LID was completely blocked by pretreatment of 5-HT1A receptor antagonist,indicating the role of 5-HT1A receptor.Furthermore,we designed and synthesis a dual dopamine/5-HT1A receptor agonist MCL-135,which also exhibits a significant relief on LID while elicits its antiparkinsonian action.Conclusions 5-HT1A receptor plys an important role in the development of LID,targeted to dual dopamine/5-HT receptor may represent a promising strategy for drug design and discovery in LID and TD treatment.

Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial

Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD patients.

Effects of Estradiol on 5-HTsA and 5-HT2c Receptor Immunolabeling in Rat Hippocampus

Steroid hormones participate in the modulation of serotonergic transmission, including the regulation of synthetic and metabolic enzyme production, as well as receptor and transporter activity. The changes of 5-HT5A and 5-HT2c immunolabeling induced by steroids in the hippocampus ofovariectomized rats were studied in this work. Densitometric analysis in rat hippocampi were carried out for adjacent brain coronal immunolabeled sections after treatment with subcutaneous injections of vehicle, estradiol, progesterone or the combination of both steroids in ovariectomized rats. Exposure to estradiol and the combination of estradiol and progesterone significantly reduced the 5-HT5A-like immunosignal in the CA 1 region while progesterone did not induce changes. On the other hand, exposure to the combination of estradiol and progesterone or estradiol alone increased the 5-HT2c immunosignal in the same region. These results indicate that estradiol is involved in the discrete regulation of serotonin receptors 5-HT5A and 5-HT2c in rat hippocampus.

Role of 5-HT2A Receptors in Immunomodulation in Animal Models of Aggressive Behavior

Serotonin 5-HT2A receptors are playing an important role in the pathophysiology of aggressive behaviors and in the control of immune function. In the present study, we analyzed the effects of activation and blockade of 5-HT2A receptors with selective ligands on the immune response formation in animals with aggressive behaviors induced by genetic factors (rats selected for the increased aggressiveness toward human) or by chronic social stress (mice of the CBA/Lac strain engaged in 10 days of social confrontations). Activation of 5-HT2A receptors with DOI at 1.0 mg/kg reduced the immune response level both in aggressive rats and mice compared to the corresponding vehicle-treated groups, while DOI administration did not alter the immune reaction in nonaggressive animals. The blockade of 5-HT2A receptors with ketanserin at 1.0 mg/kg resulted in immunostimulation both in mice of the CBA strain not subjected to social stress (the controls) and in nonaggressive rats selected for elimination of aggressiveness. On the other hand, its administration to CBA mice demonstrating offensive aggression enhanced the immune reaction, while the same dose of ketanserin did not modify the immune response level in rats with genetic predisposition to the increased defensive aggression. Thus, our data suggest that the role of 5-HT2A receptors in immunomodulation depends on the specific type of aggression that may be taking into account in the treatment of some neuropsychiatric disorders with the antipsychotic drugs and antidepressants targeting 5-HT2A receptors.

S1-2 The 5-HT6 Receptor-Related Mechanism for the Cognition-Enhancing Properties of Hypidone Hydrochloride(YL-0919),A Novel Protential Antidepressant

Hypidone hydrochloride(YL-0919),the 5-HT1A/6 agonists and 5-HT reuptake inhibitor,is a novel potent antidepressant with original chemical structure.Previous studies confirmed that YL-0919 has significant antidepressant-and anxiolytic-like effects.Compared with first-line antidepressants,YL-0919 possesses rapid-onset and cognition-enhancing advantages without causing sexual disorders.Recently,it has been found that it has high affinity with 5-HT6 receptor.Objective:To study the target characteristics of YL-0919 to 5-HT6 receptors,and to explore the relationship between the 5-HT6 receptor and the cognition-enhancing,antidepressant/anxiolytic-like effects of YL-0919 and targeting mechanisms.Methods:The radioligand binding inhibition test and[35S]-GTPγS binding assay were used to evaluate the binding affinity of YL-0919 to 5-HT6 receptor in rat striatum,transient CHO cell line and stable Hela cell lines.Novel object recognition(NOR),Morris water maze(MWM)and step-down test(SD)were used to evaluate the cognition-enhancing activity of YL-0919,and the selective 5-HT6 receptor antagonist SB271046 was used to evaluate the relationship between behavioral improvement caused by YL-0919 and 5-HT6 receptor activation.To study the 5-HT6 receptor related mechanisms of YL-0919,the competitive immunofluorescence assay were used to examine the cAMP level in h5-HT6 receptor-expressed in the Hela cells Results:①Radioligand competitive binding experiments showed that YL-0919 had high binding affinity with 5-HT6 receptors in the rat striatum,the CHO cells transiently expressed the h5-HT6 receptor and the Hela cells stably expressed the h5-HT6 receptor,with Ki of 10.72,14.76 and 28.12 nM respectively;[35S]-GTPγS showed full agonist characteristics of YL-0919 in striatum and cells,with EC50 of 71.23,64.73 and 52.92 nM respectively,and the maximum efficiency(Emax)reached 100%which is the same to the 5-HT6 receptor agonist WAY208466,suggesting that YL-0919 is a full 5-HT6 receptor agonist.②Cognitive-related behavioral tests showed that subchronic oral administration of YL-0919(1.25~2.5 mg·kg-1)could significantly increase the recognition index in NOR,the entries and duration in the target quadrant,the entries crossing the platform in WMW,shortened the first time crossing the platform in MWM and the step-down latency in SD,suggesting the cognitionenhancing effects of YL-0919;compared with Vilazodone,the partial agonist of 5-HT1A receptor and 5-HT reuptake inhibitor,which of no such functions;Further study showed that 5-HT6 receptor antagonist SB271046(10 mg·kg-1)completely blocked the cognition-enhancing effects of YL-0919 without affecting the cognitive activity itself,suggesting that 5-HT6 receptor activation might be its underlying mechanisms;③Mechanism study found that YL-0919 could significantly increase cAMP levels in the Hela cells stably-expressed the h5-HT6 receptor,which could be dose-dependent blocked by SB271046.Conclusion:YL-0919 is a full agonist of 5-HT6 receptor.YL-0919 showed significant cognition-enhancing effects in various kinds of animal models,and its underlying important mechanism might be activating 5-HT6 receptor.In addition,enhancing downstream cAMP-CREB signaling pathway of 5-HT6 receptor might at least partially mediate the above process.Moreover,5-HT6 receptor activation might also be one of the mechanisms of antidepressant-and anxiolytic-like effects of YL-0919.In conclusion,this study confirmed the 5-HT6 receptor-related mechanisms of YL-0919,the 1.1 types of antidepressants,laying the experimental foundation for developing novel antidepressants with cognition-enhancing effects.

新型5-HT_(1A)受体激动和5-HT重摄取抑制双重活性化合物YL-0919抗抑郁作用的行为学评价

目的研究兼有5-HT1A受体激动和5-HT重摄取抑制双重活性化合物YL-0919的抗抑郁作用。方法分别采用小鼠悬尾实验、小鼠强迫游泳实验、小鼠自发活动实验和大鼠获得性无助模型,观察不同剂量（0.625、1.25、2.5和5mg/kg）YL-0919的抗抑郁作用。结果在小鼠悬尾实验和小鼠强迫游泳实验中,单次灌胃给予YL-0919（0.625～2.5mg/kg）能够显著缩短小鼠悬尾不动时间和游泳不动时间;在小鼠自发活动实验中,YL-0919在上述剂量范围对自发活动无影响;在大鼠获得性无助模型上,灌胃给予YL-0919〔0.625～1.25mg/（kg·d）,1~4d〕能显著减少逃避失败次数。结论 YL-0919在小鼠和大鼠模型上具有明确的抗抑郁活性,并且在抗抑郁的有效剂量范围内无中枢兴奋和抑制作用,具有成为新型抗抑郁药物的研发潜力。

3-(2,3-二氢苯并呋喃-5-基)丙酸的合成

对甲苯酚在无水碳酸钾作用下与2-溴乙醛缩二乙醇缩合后经Friedel-Crafts反应、NBS溴代、与乌洛托品进行Sommelet反应,得苯并呋喃-5-甲醛,与丙二酸缩合后经10%钯炭在常压下催化氢化还原得雷美替胺的关键中间体3-(2,3-二氢苯并呋喃-5-基)丙酸,总收率约49%。

3-(3-氯-1,2,5-噻二唑-4-基)吡啶的合成工艺改进

以3-吡啶甲醛为原料,与氰化钠、一氯化硫反应合成选择性M1受体激动剂占诺美林的关键中间体3-(3-氯-1,2,5-噻二唑-4-基)吡啶,目标化合物的结构经1H-NMR谱确证。改进后的工艺操作简单,反应条件温和,收率由文献报道的40%提高到52%,更适合工业化生产。

1-[2-(2-Methoxyphenylthio) benzyl]-4-arylpiperazines derivatives:Synthesis and evaluation for dual 5-HT_(1A)/SSRI activities

A series of 1-[2-（2-methoxyphenylthio） benzyl]-4-arylpiperazines derivatives was designed and synthesized based on 5-HT1A/ SSRI drugs design strategies. The synthesized compounds were evaluated for their dual 5-HT1A/5-HTT activities. 2007 Ai Jun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Heat-Killed <i>Lactobacillus brevis</i>SBC8803 Induces Serotonin Release from Intestinal Cells

Previously, we reported that changes induced in autonomic neurotransmission in rats by Lactobacillus brevis SBC8803 may be mediated by serotonin 3 (5-HT3) receptors. In this study, we evaluated the effects of heat-killed L. brevis SBC8803 on serotonin (5-HT) releasing from intestinal cells. In the in vitro study, L. brevis SBC8803 stimulated 5-HT release from cultured rat endocrine RIN-14B cells (SBC8803 vs. sterile water;P in vivo study, 2 mg of heat-killed L. brevis SBC8803 was administered using a stomach sonde (feeding needle) to C57BL/6J mice. Analysis of plasma by ELISA showed gradually increase in 5-HT concentrations (0 min vs. 60 min;P ex vivo cultured intestinal loops composed of duodenum and part of the jejunum, from C3H/HeN and C57BL/6J male mice indicated that L. brevis SBC8803 effectively induced 5-HT release (SBC8803 vs. sterile water;P L. brevis SBC8803 may stimulate 5-HT release from mouse intestinal cells such as enterochromaffin cells.

Molecular signaling of 5-HT_1Aand presence of serotonergic cells in the fetal cerebral cortex

Early appearance of the serotonergic system in the fetal brain and the various effects of serotonin (5-HT) on brain morphogenesis, have given support to a neurotrophic role of serotonin. This function of serotonin is accomplished through a system of serotonin nerve terminals in the target regions that involves various 5-HT receptors. In visual, auditory and somatosensory cortex an early and intense serotonergic innervation is particularly important. The neuronal somata of these terminals are normally located in the mesencephalon and they have not been observed in the maturing cerebral cortex, neither in the adult brain. By using immunolabeling techniques, fluorescence and confocal microscopy, we observe the presence of both, 5-HT terminals and 5-HT cells in mesencephalon (Me, E17) and in the neopallium (Np, E13-E16) cocultures. Cells immunopositive to 5-HT and to tryptophan-5-hydroxilase are also observed in the Np on day 12 of culture. These results concerning the unexpected presence of serotonergic cells in the fetal cerebral cortex are interesting and may be of importance in corticogenesis. As it happens with other elements of the serotonergic system, the presence of these phenotypically serotonergic cells in the early cerebral cortex may be transitory and probably supporting cortex maturation processes. The molecular signaling path of the 5-HT1A receptor has also been identified.

Changes of Serotonin （5-HT）, 5-HT2A Receptor, and 5-HT Transporter in the Sprague-Dawley Rats of Depression, Myocardial Infarction and Myocardial Infarction Co-exist with Depression

Background： To evaluate whether serotonin （5-HT）, 5-HT2A receptor （5-HT2AR）, and 5-HT transporter （serotonin transporter [SERT]） are associated with different disease states of depression, myocardial infarction （MI） and MI co-exist with depression in Sprague-Dawley rats. Methods： After established the animal model of four groups include control, depression, MI and MI with depression, we measured 5-HT, 5-HT2AR and SERT from serum and platelet lysate.Results： The serum concentration of 5-HT in depression rats decreased significantly compared with the control group （303.25 ± 9.99 vs. 352.98 ±13.73; P =0.000）, while that in MI group increased （381.78 ±14.17 vs. 352.98 ±13.73; P = 0.000）. However, the depression ＋ MI group had no change compared with control group （360.62 ±11.40 vs. 352.98 ±13.73; P = 0.036）. The changes of the platelet concentration of 5-HT in the depression, MI, and depression ＋ MI group were different from that of serum. The levels of 5-HT in above three groups were lower than that in the control group （380.40 ± 17.90, 387.75 ±22.28,246.40 ±18.99 vs. 500.29 ±20.91 ; P = 0.000）. The platelet lysate concentration of 5-HT2AR increased in depression group, MI group, and depression ＋ MI group compared with the control group （370.75 ±14.75,393.47 ±15.73,446.66 ±18.86 vs. 273.66 ±16.90; P= 0.000）. The serum and platelet concentration of SERT in the depression group, MI group and depression ＋ MI group were all increased compared with the control group （527.51 ±28.32, 602.02 ±23.32, 734.76 ±29.59 vs. 490.56 ±16.90; P 0,047, P = 0.000, P = 0.000 in each and 906.38 ±51.84, 897.33 ±60.34, 1030.17 ±58.73 vs. 708.62 ±51.15; P = 0.000 in each）. Conclusions： The concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression. Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.

5-羟色胺受体、输送体和有关药物

综述了５－羟色胺（５－ＨＴ）的受体及其亚型的生理作用。并对以抗焦虑药丁螺环酮为代表的５－ＨＴ１Ａ受体激动剂、以抗抑郁药氟西汀为代表的作用于５－ＨＴ输送体的选择性５－ＨＴ再摄取抑制剂、以偏头痛治疗药舒马曲坦为代表的５－ＨＴ１Ｄ受体激动剂和以止吐药奥丹西隆为代表的５－ＨＴ３受体拮抗剂进行了介绍。

5-HT_(1A)和5-HT_(3)受体在七氟烷诱发老龄大鼠脑神经毒性中的作用

目的:5-羟色胺受体(5-HT_(1A)和5-HT_(3)受体)在七氟烷诱发老龄大鼠脑神经毒性中的作用。方法:清洁级健康雄性SD大鼠24只,18~20月龄,体重600~750 g,采用随机数字表法分为3组(n=8):分别吸入50%O_(2)(C组)、1.5%七氟烷+50%O_(2)(LS组)及3%七氟烷+50%O_(2)(HS组),持续2 h。于吸入七氟烷前1 d及结束后1 d时行旷场实验,记录中央格停留时间、跨格次数和站立次数;于吸入七氟烷前6 d时及结束后第1天行水迷宫实验,记录逃避潜伏期、游泳总距离和穿越平台次数。行为学实验结束即刻取海马组织,采用RT-PCR法和免疫组化法检测5-HT_(1A)和5-HT_(3)受体的mRNA表达水平及阳性细胞数。结果:与C组比较,HS组中央格停留时间延长,跨格次数及站立次数减少,逃避潜伏期延长,游泳总距离增加,穿越平台次数减少,5-HT_(1A)和5-HT_(3)受体的mRNA表达下调,阳性细胞数减少(P<0.05)。结论:七氟烷诱发老龄大鼠脑神经毒性的机制可能与下调5-HT_(1A)和5-HT_(3)受体活性有关。