精神分裂症伴强迫症状的临床特征对照研究

目的了解伴强迫症状的精神分裂症临床特征。方法采用自编的调查表对659例门诊精神分裂症患者做问卷调查及病案资料进统计行分析。结果①强迫症状的发生率为18.5%(122/659)。②伴强迫症状组待业率高于不伴强迫症状组(P=0.04);家族中强迫症、其他精神障碍除精神分裂症、强迫症外、强迫性格多于不伴强迫症状组(P=0.00～0.04);伴强迫症状组患者病前道德观念强、注意细节、追求完美、按部就班、小心谨慎的性格特征突出(P=0.00～0.04)。(3)与不伴有强迫症状的精神分裂症比较,伴强迫症状患者首次发病年龄早(P<0.001);起病形式以慢性者多(P=0.01);发作3次以上者多(P=0.01);处于康复期者少(P<0.001);病情严重程度(CGI-SI)得分高(P<0.001)。讨论伴有强迫症状的精神分裂症患者病前多具强迫性格,家族中有较多的强迫症及强迫性格者,首次发病年龄较早,多以慢性起病,发作次数较多,病情较重。伴有强迫症状的精神分裂症患者更难治,缓解率明显低于不伴有强迫症状的精神分裂症患者,且前者预后较差,其社会功能削弱较多。     

N-乙酰-5-羟色胺的电化学检测研究

采用方波溶出伏安法(OSWSV),建立了N-乙酰-5-羟色胺的—种新型快速、灵敏的测定体系。实验研究了富集条件、pH值对方波溶出伏安法对N-乙酰-5-羟色胺的影响。在pH=9.33的硼砂-氢氧化钠缓冲液中,N-乙酰-5-羟色胺在约0.2V(vs.Ag/AgCl)电位处产生一个阳极氧化峰,峰电流与浓度在1.0×10-7~1.0×10-4mol.L-1范围内成线性关系,N-乙酰-5-羟色胺检测限为1.2×10-8mol.L-1。进行尿样样品测定,回收率为81.8%,结果良好。     

肝脏5-羟色胺相关系统与肝脏疾病

本文综述了肝脏5-羟色胺相关系统与肝损伤、肝再生、非酒精性脂肪肝及非酒精性脂肪性肝炎的关系,展望了5-羟色胺受体、转运体等作为新型治疗肝脏疾病的作用靶点的潜力.     

5-羟色胺与创伤后应激障碍的研究进展

创伤后应激障碍(posttraumatic stress disorder,PTSD)是当机体遭受威胁生命或者强烈精神创伤后发生的疾病。近年来研究发现,5-羟色胺(5-HT)可能通过5-羟色胺转运体 (SERT)、5-HT受体(主要包括5-HT 1A 、5-HT1B、5-HT2A和5- HT2C受体),以及多巴胺、去甲肾上腺素等神经递质相互作用,参与PTSD的发生,该文就此进行综述。     

5-羟色胺系统与药物成瘾的关系研究进展

1 前言 药物成瘾是一种涉及到中枢神经系统功能变化的精神疾病,研究证明与多种神经递质密切相关,如多巴胺(dopamine,DA)系统在药物奖赏效应中的作用.5-羟色胺(serotonin,5-HT)系统起源于中缝核投射到黑质纹状体、边缘系统和皮层.     

5-羟色胺免疫电极的研制和应用

研制了电位型无标记５－羟色胺（５－ＨＴ）免疫电极。以偶联法制备抗体膜,结合抗原后的复合膜与空白膜的△Ｅ值与５－ＨＴ的浓度成线性关系。电极的线性范围为１．１８×１０－７～６．２７×１０－６ｍｏｌ／Ｌ,检测下限为１．１２×１０－７ｍｏｌ／Ｌ,斜率为－１３．０８ｍｌ,相关系数ｒ＝－０．９９８４,对血中其他物质选择性良好,抗体膜片一次性使用,以标准曲线法测定了牛血小板中５－ＨＴ浓度。     

学龄儿童偏头痛与血小板和血浆5-羟色胺关系分析

近年来,偏头痛的发病机制和治疗方面的研究取得很大进展,认为这是一种多灶性疾病。不仅有颅内外血管张力的改变,还有中枢神经系统(CNS)、胃肠道、内分泌、血小板等多方面病理生理改变,并且认为这些改变均可以用体内5-羟色胺(5-HT及其受体异常来解释,所以偏头痛和5-HT的关系重新受到重视。血小板在血栓和止血过程中能够释放5-HT,目前还发现血小板在选择性摄取、贮存、释放、代谢某些单胺类介质和肽类物质方面与中枢神经元具有相同的机制。但有关以血小板作为中枢5-HT能神经元模型进行学龄儿童偏头痛方面的研究,国内尚未见有关报道,现将我们取得的初步结果报道如下。     

外周5-羟色胺系统与糖尿病及其并发症防治关系的研究进展

糖尿病及相关并发症严重威胁人类的健康,但由于其发病机制未被阐明,阻碍了抗糖尿病药物的开发与推广。临床和动物实验结果表明5-羟色胺（5-hydroxytryptamine,5-HT）和糖尿病的发生、发展有紧密的关联,随着研究的不断深入,外周5-HT系统显示出作为治愈糖尿病重要靶点的潜力。本文首先对外周5-HT在糖尿病及其并发症发生和发展过程中的作用进行阐述,接着对5-HT调节糖尿病的机制进行探讨,随后对与糖尿病并发症相关的5-HT受体进行系统的总结,最后对如何利用药物通过5-HT系统防治糖尿病提出展望。     

马鞭草醇提液的抗炎作用与组胺、5-羟色胺的关系

目的观察马鞭草醇提液的抗炎作用与组胺、5-羟色胺的关系方法用二甲苯致小鼠耳廓肿胀,通过放免法测定耳廓组织中组胺和5-羟色胺的含量。结果马鞭草醇提液能显著降低小鼠耳廓组织中组胺、5-羟色胺的含量。结论马鞭草醇提液的抗炎作用可能与其抑制组胺、5-羟色胺的合成与释放有关。     

5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option

A role of the HTR3A-E genes in obsessive-compulsive disorder (OCD) can be expected based on promising effects of 5-HT3 receptor antagonists as adjunctive treatment of OCD. We therefore genotyped six common coding or promoter variants within the HTR3A-E genes in a case-control-sample consisting of N=236 OCD patients and N=310 control subjects and in N=58 parent–child-trios. Given the heterogeneous OCD phenotype, we also investigated OCD symptom dimensions and cognitive endophenotypes in subsamples. OCD patients scoring high for the washing subtype were significantly more likely to carry the c.256G-allele of the HTR3E variant rs7627615 (p=0.0001) as compared to OCD patients low for this symptom dimension. Visual organization was impaired in OCD patients and unaffected relatives as compared to healthy control subjects and carriers of the HTR3E c.256G/c.256G-genotype performed significantly worse (p=0.007). The case-control analyses revealed a nominal significant association of the HTR3D variant rs1000592 (p.H52R) with OCD (p=0.029) which was also evident after combination of the case-control and the trio-results (p=0.024). In male subjects, the variant rs6766410 (p.N163K) located in the HTR3C was significantly associated with OCD (p=0.007). The association findings of the HTR3C and the HTR3E remained significant after correction for the number of variants investigated. These findings indicate a role of common variants of the HTR3A-E genes in OCD and OCD-related phenotypes and further support the use of 5-HT3 receptor antagonists as novel treatment options. The HTR3E gene is a novel candidate gene impacting on the individual expression of OC symptoms and OCD-related cognitive dysfunction.     

The role of 5-HT on the cardiovascular and renal systems and the clinical potential of 5-HT modulation

The main peripheral sources of 5-hydroxytryptamine (5-HT) are as a neurotransmitter and local hormone in the gastrointestinal tract, and stored in circulating platelets and pulmonary neuroepithelial bodies. 5-HT has been shown to have many possible physiological and pathophysiological roles on the cardiovascular and renal systems. Thus, 5-HT may contribute to valvular heart disease, coronary artery disease, pulmonary hypertension, pulmonary embolism, pre-eclampsia, peripheral vascular disease and diabetic nephropathy. Consequently, modulators of the 5-HT system have diverse clinical potential. For instance, selective 5-HT subtype 3 receptor (5-HT₃) antagonists may have potential in the treatment of the pain associated with myocardial infarction. MCI-9042 (sarpogrelate) or other 5-HT_2A antagonists may have clinical potential for the treatment of vasospastic angina, ischaemic heart disease, reperfusion injury and hindlimb ischaemia. Several modulators of 5-HT (5-HT transporter inhibitors, 5-HT_1B and _2B antagonists) may have potential alone or in combination in the treatment of pulmonary hypertension. In hypertension, agonists at the 5-HT₇ and antagonists at the 5-HT_2B may reduce blood pressure, and in diabetes, sarpogrelate may protect against nephropathy.     

Antagonism of baclofen's effects on rat striatal 5-HT metabolism: A model for 5-HT agonistic properties?

The increase in the rat striatal concentration of 5-hydroxyindoleacetic acid (5-HIAA) elicited by baclofen was antagonized by the 5-HT antagonists pipamperone (10/30 mg/kg i.p.), cyproheptadine (30 mg/kg i.p.), methiothepin (1 mg/kg i.p.), and GP 50 302 (1/3 mg/kg i.p.), but not by cinanserin (1–30 mg/kg i.p.), pizotifen (1–10 mg/kg i.p.), spiroperdol (0.1–1 mg/kg i.p.), or haloperidol (0.1–1 mg/kg i.p.). The 5-HT agonists, m-chlorophenylpiperazine (1 mg/kg i.p.) and MK 212 (3/10 mg/kg i.p.) also showed an antagonistic effect. Methysergide (5–20 mg/kg i.p.) and quipazine (2.5/5 mg/kg i.p.) were previously shown to act similarly, whereas mianserin (5–20 mg/kg i.p.) was inactive and methergoline at lower doses (0.25–0.5 mg/kg i.p.) increased the effect of baclofen, which was reversed at higher doses (1 mg/kg i.p.). The alterations by these compounds of the 5-HT increase elicited by baclofen were more or less similar; however, they were less clear-cut and occurred at higher doses. These interactions were not the result of interferences of the compounds with the absorption, distribution, or metabolism of baclofen nor with its effect on the nigrostriatal dopaminergic system, since the increase in dopamine concentrations it caused was not affected by any of the compounds. A comparison of our results with published data on the antagonism of 5-hydroxytryptophan-induced head twitches, on spiroperidol or 5-HT displacement, on 5-HT-stimulated adenylate cyclase, and with electrophysiological results suggests that the antagonistic effect of compounds interfering with the 5-HIAA elevating action of baclofen is not related to 5-HT receptor blocking properties of these drugs, Instead, it seems to be much more related to 5-HT agonists properties. It is speculated that this model might reveal presynaptic agonistic properties of drugs, but more data are needed to confirm or reject this.     

Synergism between 5-HT1B/1D and 5-HT1A receptor antagonists on turnover and release of 5-HT in guinea-pig brain in vivo

The effects on 5-HT turnover (5-HIAA/5-HT ratio) and extracellular 5-HT and 5-HIAA levels (in vivo microdialysis in freely moving animals) were analysed in guinea-pig brains following the 5-HT_1B receptor antagonist, GR 127935 {N-[4-methoxy-3-(4-methyl-1-piper_{azinyl)phenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-}yl) [1,1-biphenyl]-4-carboxamide}, or the 5-HT_1A receptor antagonist, WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride), administered alone or in combination. GR 127935, injected alone, increased 5-HT turnover with maximal effects approximately 50% above the control levels in the four brain regions examined (hypothalamus, hippocampus, striatum and frontal cortex). GR 127935 significantly increased extracellular concentrations of 5-HT and 5-HIAA in frontal cortex (40%), whereas 5-HIAA, but not 5-HT, was elevated in striatum (20–30%). WAY-100635 did not significantly change 5-HT turnover but caused a small significant increase in the extracellular 5-HT and 5-HIAA concentrations in both striatum and frontal cortex. The combined treatment with GR 127935 and WAY-100635 resulted in an increased 5-HT turnover reaching maximal effects of 70–90% above the control values in all brain regions tested and produced a significant elevation of striatal and frontal cortex extracellular 5-HT (40% and 60%, respectively) and 5-HIAA (60% and 70%, respectively) concentrations. The synergistic effect of the two receptor antagonists on the 5-HT turnover and the terminal release of 5-HT indicate somatodendritic 5-HT release and stimulation of inhibitory 5-HT_1A receptors at this level. Extracellular 5-HIAA seems to be a better marker than 5-HT itself for the evoked 5-HT release when the reuptake mechanism is intact. Received: 2 September 1998 / Accepted: 19 November 1998     

5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum

Summary Agonist-induced desensitization has been utilized to discriminate and independently isolate the neuronal excitatory receptors to 5-hydroxytryptamine (5-HT) in the guinea pig ileum (5-HT₃ and putative 5-HT₄ receptors). Electrically stimulated longitudinal muscle myenteric plexus preparations, and non-stimulated segments of whole ileum were used. Exposure to 5-methoxytryptamine (10 mol/l) inhibited completely responses to 5-HT at the putative 5-HT₄ receptor without affecting 5-HT₃-mediated responses. Conversely, exposure to 2-methyl-5-HT (10 mol/l) inhibited completely responses to 5-HT at the 5-HT₃ receptor without affecting putative 5-HT₄-mediated responses. The inhibition with 5-methoxytryptamine and 2-methyl-5-HT, either alone or in combination, appeared selective as responses to KCI, DMPP, carbachol, histamine, and substance P were unaffected or only very slightly modified. Furthermore, the pA₂ values for ICS 205–930 at the putative 5-HT₄ (pA₂ = 6.2 to 6.5) and 5-HT₃ (pA₂ = 7.6 to 8.1) receptors (estimated in the presence of 2-methyl-5HT and 5-methoxytryptamine, respectively) were consistent with those estimated in the absence of desensitization.5-Methoxytryptamine, but not 2-methyl-5-HT, suppressed completely but reversibly the concentration-effect curve to renzapride, suggesting that responses to this agent are mediated exclusively via agonism at the putative 5-HT₄ receptor.It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT₄ receptor from the 5-HT₃ receptor in guinea pig ileum. This finding is of importance as no selective antagonist exists for the putative 5-HT₄ receptor. Furthermore, the presently described method of agonist-induced desensitization and 5-HT receptor discrimination may be useful for the identification and characterization of the putative 5-HT₄ receptor in other tissues and species. Send offprint requests to D. E. Clarke at the above address     

Pharmacological characterization of the 5-HT1A, 5-HT2 and 5-HT3 receptors in the bovine ciliary muscle

We aimed to investigate the effects of serotonin (5-hydroxytryptamine, 5-HT) on the bovine ciliary muscle and subsequently to characterize and identify the subtypes of 5-HT receptors involved in the serotonin-evoked contractility muscle. The binding of [3H]ketanserin, [3H]granisetron and [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) was analyzed. All labelled compounds bound with high affinity to a single site in the membrane preparations studied. The affinity (K(d)) of the binding site was 7.5+/-1.2 nM for [3H]ketanserin, 6.9+/-0.8 nM for [3H]granisetron and 4.4+/-0.31 nM for [3H]8-OH-DPAT. The density of receptors (B(max)) was 1062+/-43.0 fmol/mg protein for [3H]ketanserin, 566+/-2.32 fmol/mg protein for [3H]granisetron and 205+/-4.63 fmol/mg protein for [3H]8-OH-DPAT. The serotonin-induced contraction appeared to be competitively antagonized by ketanserin (0.1, 1 and 10 microM) and ondansetron (0.1, 10 and 100 microM) which produced a pA(2) value of 8.5+/-0.12 and 8.0+/-0.19, respectively. 8-OH-DPAT and 5-carboxamidotryptamine (5-CT) proved to be completely ineffective. We conclude that serotonin induces bovine ciliary muscle contraction via 5-HT(2) and 5-HT(3) receptors while the 5-HT(1A) receptors, although present, do not mediate the contractile response.     

5-HT3- and 5-HT2C-antagonist properties of cyamemazine: significance for its clinical anxiolytic activity

Rationale: Cyamemazine is a neuroleptic compound which possesses anxiolytic properties in humans. On the other hand, 5-HT₃- and 5-HT_2C-receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types. Objective: The present study was undertaken to establish whether cyamemazine antagonizes 5-HT₃- and/or 5-HT_2C-mediated responses, and whether it compares with reference compounds. Methods: Cyamemazine was tested for its ability to antagonize: (i) 5-HT₃-dependent contraction of the isolated guinea-pig ileum and bradycardic responses in the rat and (ii) 5-HT_2C-dependent phospholipase C (PLC) stimulation in rat brain membranes. Results: In isolated guinea-pig ileum, cyamemazine potently and competitively antagonized 5-HT-dependent contractions (pA₂=7.52±0.08; n=5). In this test, cyamemazine was 5–7 times more potent (pIC₅₀=6.75±0.13) than tropisetron (pIC₅₀=6.02±0.04). In rats, cyamemazine i.v. antagonized 5-HT-dependent bradycardic responses with ID_50%=3.2±1.5 mg/kg (n=4). Finally, in rat brain membranes cyamemazine antagonized 5-HT_2C-dependent PLC stimulation with K_i=424 nM (mianserin exhibits a K_i=113 nM). Conclusions: Cyamemazine behaves as an antagonist at both 5-HT₃- and 5-HT_2C-receptors, which compares well with reference compounds. These 5-HT₃- and 5-HT_2C-antagonistic actions of cyamemazine can be involved, at least in part, in its beneficial therapeutic actions in anxiety disorders. Received: 19 May 1999 / Final version: 3 August 1999     

Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system

The present review gives an overview on the serotonin (5-hydroxytryptamine; 5-HT) system, its receptors and their relationship to central nervous system physiology and disorders. Additionally, we also introduce the recent knowledge about the 5-HT receptor ligands in preclinical research, clinical trials and as approved drugs.     

Accumulation of 5-HT in non-terminal axons after p-chloro-N-methylamphetamine without degeneration of identified 5-HT nerve terminals.

The effect of a single injection of d,1-p-chloro-N-methylamphetamine (PCMA) on 5-hydroxytryptamine (5-HT)- containing neurons in rat brain was investigated using fluorescence histochemical, electron microscopic and biochemical methods. PCMA caused in a dose-dependent manner (from 4.3 mg/kg), an increase of formaldehyde-induced indoleamine (IA) fluorescence in swollen non-terminal axons during the first 6 days and, in contrast, a diminution of IA fluorescence in nerve terminal regions for up to 42 days after treatment. These changes did not appear to be the result of destruction of 5-HT nerve terminals since at all time intervals investigated (12 h to 42 days), the fine structure and frequency of supra-ependymal 5-HT nerve terminals were unaffected. Moreover, no degenerating nerve terminals were observed in the suprachiasmatic nucleus. A marked transient decrease of IA fluorescence on day 2 in the 5-HT cell bodies B3-B9 was not followed by obvious morphological changes up to 42 days after PCMA. Therefore, the reduced 5-HT content of brain up to 42 days after treatment seems not to be due to a destruction of 5-HT neurons. Moreover, the damage to non-terminal 5-HT axons, as indicated by the 5-HT accumulation, seems not to be severe, at least not to those axons projecting to the cerebral ventricles and suprachiasmatic nucleus, since no degeneration of 5-HT nerve terminals was observed at any of the times investigated.     

Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive-compulsive disorder

Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT_1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT_1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg/kg of IPS or placebo were given under double-blind, random-assignment conditions to ten patients before and during FLX treatment. The ability of IPS to induce hypothermia and ACTH/cortisol release was significantly attenuated during chronic FLX as compared to the pretreatment IPS challenge. The behavioral effects of IPS, though minimal, were less pronounced during FLX treatment. While FLX was effective in reducing the severity of OC symptoms, no significant correlation between attenuation of 5-HT_1A receptor-mediated functional measures and FLX-induced improvement in OC symptoms was detected. These findings are consistent with the development of adaptive hyporesponsivity of the 5-HT_1A receptor-effector system complex possibly involving subsensitivity of the 5-HT_1A receptor itself and/or decreased functional activity of the postreceptor signal transduction. Modulation of 5-HT_1A receptor-effector system function may be critical to the antidepressant/anti-OC efficacy of 5-HT reuptake inhibitors.Part of this work was presented at the 17th Congress of the CINP, Kyoto, Japan, September 10–14, 1990