Tau蛋白激酶及其抑制剂的研究进展

阿尔茨海默病是一种常见的原发性中枢神经系统退行性疾病,其病理学机制较为复杂。研究发现,过度磷酸化的Tau蛋白聚集是阿尔茨海默病神经病理学损伤的一个标志性特征,因此利用药物调节Tau蛋白的过度磷酸化成为治疗阿尔茨海默病的一种有效策略。本文重点介绍了影响Tau蛋白过度磷酸化的两种重要蛋白激酶GSK-3β(糖原合成酶激酶-3β)和CDK5(细胞周期素依赖蛋白激酶5),以及近年来针对这两种激酶设计的不同结构类型的小分子抑制剂,并对其构效关系进行综述。     

苍术内酯对骨关节炎大鼠软骨损伤修复和软骨细胞凋亡的影响

目的 探讨苍术内酯（AT）对骨关节炎大鼠软骨损伤修复和软骨细胞凋亡的影响及其可能作用机制。方法 60只7～8周龄SPF级雄性SD大鼠,48只大鼠采用前后交叉韧带断离术建立骨关节炎（OA）模型,造模成功大鼠采用随机分为模型组、AT低、中、高剂量组,各12只,另设对照组（12只）。AT低、中、高剂量组腹腔注射5、10、20 mg/kg AT,对照组及模型组给予等量生理盐水,连续30 d。观察大鼠软骨组织形态计算Mankin’s评分;酶联免疫吸附试验（ELISA）检测各组大鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)水平;苏木精-伊红（HE）染色观察软骨组织病理学变化;TUNEL法检测大鼠软骨组织细胞凋亡情况;实时荧光定量逆转录聚合酶链式反应（qRT-PCR）检测大鼠软骨组织中微RNA-98-5p(miR-98-5p)表达、高迁移率族蛋白2(HMGA2)、糖原合成酶激酶-3β(GSK-3β)mRNA表达;蛋白质印迹法（Western blotting）检测大鼠HMGA2、GSK-3β、凋亡蛋白B细胞淋巴瘤因子2(Bcl-2)、Bcl-2相关...     

5-羟色胺5-HT_(2C)受体激动剂抑制吗啡依赖小鼠纳洛酮诱导的戒断行为

目的观察5-羟色胺2C受体(5-HT2CR)激动剂WAY对吗啡依赖小鼠纳洛酮诱导戒断症状的防治作用,探讨5-HT2CR在吗啡成瘾导致的躯体依赖中的作用。方法采用Etho Vision动物行为分析系统观察5-HT2CR激动剂WAY对正常小鼠自发活动的影响;剂量递增法诱导小鼠吗啡依赖模型,观察WAY对吗啡依赖小鼠纳洛酮诱导戒断症状的影响。结果 WAY(0.5、0.75、1.0 mg·kg-1,i.p.)对小鼠自发活动没有明显影响。慢性吗啡诱导依赖小鼠运动距离、速度和跳跃等行为活动增加。WAY(0.5、0.75、1.0 mg·kg-1)和可乐定(0.2 mg·kg-1,i.p.)对吗啡依赖小鼠纳洛酮催促出现的打洞、跳跃、清理皮毛、站立、"湿狗"样抖动、摇头、清理脸部、抓挠戒断症状有明显的抑制作用(P<0.05)。结论药物激活5-HT2CR可明显的抑制吗啡依赖小鼠纳洛酮催促的戒断症状。5-HT2CR可能是潜在的治疗吗啡躯体依赖、渴求和复吸的靶点。     

帕罗西汀通过Akt/GSK3β/CREB通路对焦虑大鼠行为学的改善作用

目的 基于蛋白激酶B(Akt)/糖原合成酶激酶3β(GSK3β)/环腺苷酸反应元件结合蛋白(CREB)通路探讨帕罗西汀对焦虑大鼠行为学的影响。方法 焦虑大鼠模型采用单笼饲养且接受不确定性空瓶饮水刺激方法建立。SPF级SD雄性大鼠随机分为对照组、模型组、低中高剂量帕罗西汀组(帕罗西汀3 mg/kg、6 mg/kg、12 mg/kg)、Akt抑制剂组(Akt抑制剂Perifosine 20 mg/kg+帕罗西汀12 mg/kg),每组6只。观察大鼠攻击、探究、修饰行为;高架十字迷宫(EPM)试验记录大鼠进入开放臂次数(OE)、进入开放臂时间(OT)、进入封闭臂次数(CE)、进入封闭臂时间(CT)、向下探究次数(HD),并计算OE+CE、OE比例(OE%)、OT比例(OT%);实时荧光定量PCR法(qRT-PCR)和免疫印迹法(Western blot)检测大鼠海马组织中Akt、GSK3β、CREB mRNA及蛋白水平。结果 与对照组比较,模型组大鼠毛色干枯无光、粗糙,易被激怒,探究行为、修饰行为、攻击行为水平升高(P<0.05),OE+CE、OE%、OT%、HD水平降低(P<0...     

疏肝健脾饮对糖尿病性胃轻瘫大鼠的干预作用

目的观察疏肝健脾饮对链脲佐菌素致糖尿病性胃轻瘫大鼠的胃肠推进指标及nNOS、5-HT4R、β2-AR等指标的影响并探讨其作用机制。方法以2%链脲佐菌素(STZ)加不规则饮食4周造成糖尿病性胃轻瘫大鼠模型,将30只模型大鼠随机分为模型组和中药组,4周后中药组以相当于成人临床常用剂量的2倍灌胃给药,模型组灌胃等剂量生理盐水,1次/d,给药4周。另取10只正常大鼠作为正常组。实验通过胃肠推进指标和nNOS、5-HT4R、β2-AR免疫组化的结果观察疏肝健脾饮对糖尿病性胃轻瘫大鼠的干预作用。结果疏肝健脾饮不仅降低糖尿病性胃轻瘫大鼠的血糖,还可以明显改善胃肠推进,并改善nNOS、5-HT4R、β2-AR等指标,与模型组比较有显著性差异(P<0.05)。结论疏肝健脾饮能降低糖尿病性胃轻瘫大鼠的血糖,加速胃排空,并改善nNOS、5-HT4R、β2-AR等免疫组化指标。     

中药降糖复方水提取物对KK-Ay糖尿病小鼠骨骼肌糖代谢PI3K/Akt信号通路的影响

目的 研究中药降糖复方水提取物（WEJTD）对自发性2型糖尿病（T2DM）模型KK-Ay小鼠骨骼肌糖代谢PI3K/Akt信号通路的影响。方法 将KK-Ay小鼠按随机数法随机分为5组：模型组、盐酸二甲双胍（MH,250 mg/kg）组和WEJTD低、中、高剂量（2、4、8 g/kg）组,C57BL/6J小鼠作为对照组,每天ig给药1次,共12周,对照组和模型组ig等体积蒸馏水。给药12周后,取小鼠血清,ELISA试剂盒法检测胰岛素水平;Trizol法提取肌肉组织中的RNA,荧光实时定量PCR（qRT-PCR）检测磷脂酰肌醇激酶-3（PI3K）、蛋白激酶B（Akt）、葡萄糖转运蛋白-4（GLUT-4）、糖原合成酶激酶-3β（GSK-3β）、糖原合成酶（GS）、胰岛素受体底物（IRS-1）mRNA水平。结果 与模型组比较,WEJTD高、中剂量显著上调小鼠血清胰岛素水平、骨骼肌中IRS-1 mRNA水平（P<0.05、0.001）;高、中、低剂量均显著下调骨骼肌中GSK-3β mRNA水平,显著上调PI3K、Akt、GLUT-4、GS mRNA水平（P<0.05、0.01、0.001）。结论 中药降糖复方通过上调PI3K/Akt信号通路,减少糖原沉积,刺激骨骼肌中葡萄糖转运。     

H_(3)R拮抗剂GSK189254改善Aβ大鼠学习记忆障碍及其机制初探北大核心CSCD

目的研究组胺H_(3)受体(histamine H_(3) receptor,H_(3)R)拮抗剂GSK189254对阿尔茨海默病(Alzheimer′s disease,AD)大鼠学习记忆行为的影响并探讨其可能机制。方法选取20只成年雄性Wistar大鼠,分为对照组(n=8)、Aβ1-42组(n=6)和Aβ1-42+H_(3)R拮抗剂组(n=6)。Aβ1-42组动物侧脑室注射β淀粉样蛋白1-42(β-amyloid,Aβ1-42,0.67 g·L^(-1),5μL),连续14 d。Aβ1-42+H_(3)R拮抗剂组除同前侧脑室注射14 dAβ1-42外,同时连续28 d给予GSK189254(1 g·L^(-1),5μL)。停药1 d后,所有动物行Morris水迷宫、Y迷宫以及新事物识别行为检测。次日,以生理盐水经动物心脏灌流后取脑,左侧脑以4%多聚甲醛固定后进行免疫组化染色;右侧脑分离海马与前额叶皮层,应用高效液相串联质谱(HPLC-MS/MS)和qPCR法检测各种神经递质的含量与炎症因子的表达。结果H_(3)R拮抗剂GSK189254可以改善Aβ1-42诱导的AD大鼠学习记忆障碍行为与神经元损伤,不同程度增加海马与前额叶皮层内多种神经递质的含量,以五羟色胺(5-HT)最为明显;GSK189254虽可以降低多种炎症因子的表达,但并无明显影响。结论H_(3)R拮抗剂GSK189254可通过增加海马内5-HT释放改善AD大鼠学习记忆能力的缺失。     

二苯乙烯苷对冈田酸致NG108-15细胞Tau蛋白磷酸化的影响

目的:观察二苯乙烯苷(TSG)对冈田酸(OA)诱导致NG108-15细胞Tau蛋白磷酸化的影响,探讨该化合物抗阿尔茨海默病(AD)的可能机制。方法:以OA诱导NG108-15细胞复制AD细胞模型,采用MTT法检测经TSG低、中、高剂量(50、100、200μmol/L)预处理后的细胞存活率,采用吖啶橙/溴乙锭双染色法检测细胞凋亡情况,采用Western blotting法和逆转录-聚合酶链反应法检测细胞周期蛋白依赖性激酶5(CDK5)、糖原合成酶激酶3β(GSK3β)蛋白及其mRNA以及Tau、磷酸化Tau(p-Tau)蛋白的表达情况,采用免疫荧光法检测CDK5、GSK3β、Tau蛋白的分布情况。结果:正常对照组细胞形态正常,未见或少见CDK5、GSK3β、Tau蛋白分布。模型组可见固缩或圆珠状的早期凋亡细胞,且CDK5、GSK3β、Tau蛋白分布明显增多,其细胞存活率显著降低,CDK5、GSK3β蛋白及其mRNA的相对表达量以及p-Tau与Tau相对表达量的比值(p-Tau/Tau)均显著升高(P<0.05或P<0.01)。经TSG预处理后,各给药组早期凋亡细胞和CDK5、GSK3β、Tau蛋白分布均有所减少,其细胞存活率均显著升高,中、高剂量组细胞CDK5蛋白、p-Tau/Tau以及各剂量组细胞CDK5 m RNA、GSK3β蛋白及其mRNA的相对表达量均显著降低(P<0.05)。结论:TSG对AD模型细胞具有一定的保护作用,这种作用与其提高细胞存活率,下调磷酸激酶CDK5、GSK3β的蛋白表达和基因转录水平,抑制Tau蛋白的磷酸化有关。     

野黄芩苷对卒中后抑郁模型大鼠糖原合成酶激酶3β/β-连环蛋白信号通路的影响

目的 探讨野黄芩苷对卒中后抑郁(PSD)模型大鼠糖原合成酶激酶3β(GSK-3β)/β-连环蛋白(β-catenin)信号通路的影响.方法 用线栓法制备大鼠脑卒中模型,待脑卒中模型制备成功后,用孤养结合慢性温和不可预知应激(CUMS)建立抑郁模型.将模型大鼠按体重随机分为模型组,低、中、高剂量实验组和阳性对照组,每组1...     

快速起效抗抑郁药研发策略:单胺(5-HT)-非单胺(Glu/GABA)长反馈神经环路候选假说的提出

抑郁症已成为全球性严重的公共卫生问题,目前临床一线抗抑郁剂大多是基于经典的"单胺假说(策略)"研发的,这些药物普遍存在起效缓慢、有效率不高、损伤认知和致自杀倾向等缺陷,因此,突破经典单胺策略框架,发展快速起效、兼可增强认知和低毒副作用抗抑郁药物是目前全球性重大需求和方向。2019年,S-氯胺酮和别孕烯醇酮(brexanolone)等快速起效抗抑郁药的上市为基于N-甲基-D-天冬氨酸(NMDA)和γ-氨基丁酸A(GABA_A)等受体的非单胺策略开辟了全新的前景。目前快速起效抗抑郁药研发总体趋势主要有二:即基于优化多靶标的单胺策略(现代单胺策略)和基于谷氨酸(Glu)-GABA平衡调控的非单胺策略。根据本实验室和国外同行的研究,我们提出单胺-非单胺即"5-羟色胺(5-HT)-Glu/GABA长反馈神经环路"候选假说,认为脑内单胺调控机制(如5-HT神经元,位于中缝核)与非单胺调节机制(Glu/GABA神经元,位于前额皮质等脑区)均是快速起效抗抑郁药机制的一部分,二者共同组成长反馈神经环路,介导前额皮质和海马等效应脑区快速增强的突触可塑性。基于该环路提出5个方面抗抑郁快速起效的候选策略:①通过解除GABA中间神经元对Glu锥体神经元的抑制或直接激活Glu锥体神经元,实现快速兴奋/抑制(E/I)平衡;②借助5-HT_(1A)等受体同时调控5-HT神经元活性和兴奋/抑制平衡(同时增强单胺-非单胺环节);③直接激活哺乳动物西罗莫司(雷帕霉素)靶蛋白复合物1(mTORC1),快速增强脑源性神经营养因子(BDNF)-mTOR通路;④刺激脑内BDNF的快速释放。⑤正向变构调节GABA_A受体。希望这些思路和策略为进一步发现快速抗抑郁候选靶标提供有益的借鉴。     

Effects of donepezil on DOI-induced head twitch response in mice: implications for Tourette syndrome

Tourette syndrome (TS) is a neurological disorder characterized by persistent motor and phonic tics. Administration of the selective 5-HT(2A/2C) agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induces head twitches in mice that have been proposed to model tics seen in TS. Previous studies have demonstrated that nicotine markedly attenuates DOI-induced head twitch response (HTR). This and the reports that nicotine may have clinical efficacy in reducing symptoms of TS suggest possible involvement of the nicotinic cholinergic system in this disorder. Donepezil is an acetylcholinesterase inhibitor approved for use in mild to moderate Alzheimer's disease. The purpose of this study was to investigate whether donepezil might also reduce DOI-induced HTR, and whether its combination with nicotine might result in an additive or synergistic effect. Moreover, to elucidate the possible role of nicotinic receptors in this paradigm, the effects of mecamylamine, a nicotinic antagonist, was also evaluated. Acute and chronic administration of donepezil (0.1 mg/kg) or nicotine (0.5 mg/kg base), significantly reduced DOI-induced HTR. No additive or synergistic effects of donepezil and nicotine were observed. Acute mecamylamine administration (0.5-5.0 mg/kg) dose-dependently inhibited DOI-induced HTR. None of the mecamylamine doses blocked the inhibitory effects of donepezil or nicotine on DOI-induced HTR. These results suggest that donepezil may have therapeutic potential in treating motor tic symptoms of TS. Moreover, the action of donepezil and nicotine may be mediated through the same mechanism.     

Nimodipine can improve cerebral metabolism and outcome in patients with severe head trauma

In the present study, the effect of nimodipine was investigated in a patient with severe head trauma. Nimodipine was administered into the peripheral vein to prevent secondary neuronal damages in patients. The five patients in control group were treated according to the standard procedures without nimodipine. Other five patients in nimodipine group were treated with standard procedures plus nimodipine. Cerebral perfusion pressure (CPP), intracranial pressure (ICP), jugular venous oxygen saturation (SjvO₂), jugular lactate and glucose levels were measured. Additionally, all patients were evaluated with Glascow outcome score (GOS) before discharge. It was found that CPP (p < 0.05) and SjvO₂ (p < 0.05) were significantly higher; but, ICP (p < 0.001), jugular lactate (p < 0.05) and jugular glucose (p < 0.05) were lower in nimodipine than that of control groups. Again, GOS values were significantly higher in nimodipine than that of control groups (p < 0.05). Results of this study revealed that nimodipine can improve cerebral metabolism and outcome in patient with severe head trauma. Thus, nimodipine may be considered as a protective agent against severe head trauma related neuronal injuries.     

Salmon calcitonin induced head twitch in the rat

The intracerebroventricular administration of salmon calcitonin (sCT) to rats induced a dose-dependent increase in the number of head twitches and potentiated such a response elicited by L-5-hydroxytryptophan (L-5-HTP). Subcutaneously administered sCT was ineffective "per se" but could again potentiate the head twitch response elicited by L-5-HTP. Since these data suggest a stimulation of the brain serotonergic pathways, the obtained results support the hypothesis that some central actions of sCT may involve activation of serotonergic systems in the rat brain.     

托吡酯治疗儿童抽动秽语综合征

目的:观察托吡酯治疗儿童抽动秽语综合征(Tourettesyndrome, TS)的疗效及其不良反应。方法:将96例TS病儿分为治疗组和对照组各48例。治疗组采用托吡酯按0. 5 ~ 1. 5mg·kg-1·d-1,分2 次口服, 对照组采用硫必利100 ~400mg·d-1,分2~3次口服,疗程6mo。治疗期间每月定期门诊复诊。结果:治疗组有效率为87 %,对照组有效率为85 %。2组疗效比较差异无显著意义(P> 0. 05); 2组不良反应率相比有非常显著差异(P <0. 01)。结论:托吡酯与硫必利治疗TS疗效相似,且不良反应较硫必利明显减少,同时可有效减轻合并症状。     

机械加载可改善心肌梗死大鼠的心肌损伤

摘要：目的 探讨机械加载对心肌梗死大鼠心肌损伤的改善作用。方法 选用8周龄Wistar雄性大鼠30只,体 质量约200 g,按随机数字表法分为假手术对照组（Sham组）、心肌梗死组（MI组）和心肌梗死机械加载治疗组（MI+L 组）,每组10只,心肌梗死建模后1 d开始膝关节机械加载治疗2周。检测治疗后大鼠心电图Ⅱ导联ST段、心脏质量 指数（HMI）、左心室质量指数（LVMI）、心脏质量/胫骨长度,2,3,5－三苯基氯化四氮唑（TTC）染色检测左室舒张末内 径（LVEDD）和梗死范围;HE染色检测炎性细胞数;Masson染色检测胶原容积分数（CVF）;免疫组织化学染色检测核 因子（NF）-κB p65亚基、白细胞介素（IL）-6和基质金属蛋白酶（MMP）-9蛋白的表达。结果 与Sham组相比,心肌 梗死导致MI组心电图Ⅱ导联ST段抬高,HMI、LVMI、LVEDD、心脏质量/胫骨长度和梗死范围明显增加;机械加载治 疗后,MI+L组Ⅱ导联ST段抬高幅度下降,HMI、LVMI、LVEDD、心脏质量/胫骨长度和梗死范围较MI组明显降低（P＜ 0.05）。心脏组织学结果表明,心肌梗死导致炎性细胞数和CVF增加,通过加载治疗后,炎性细胞数和CVF明显改善 （P＜0.05）。免疫组化染色结果表明,心肌梗死导致大鼠心肌NF-κB p65、IL-6和MMP-9蛋白表达升高,机械加载能 够抑制3种蛋白的表达。相关性分析结果表明,NF-κB p65、IL-6和MMP-9三者之间表达呈正相关,三者与心室重构 指标（LVEDD、HMI、LVMI和心脏质量/胫骨长度）呈正相关。结论 机械加载可以明显改善心肌梗死大鼠心肌损伤, 该治疗作用可能与机械加载减轻心肌梗死后炎症反应和抑制心室重构有关。     

抽动-秽语综合征患者应用脑电超慢涨落技术与脑电图仪进行诊断的比较

目的探讨抽动-秽语综合征患者脑电超慢涨落（ET）的变化特点.方法对30例抽动-秽语综合征患者进行脑电超慢涨落分析仪和脑电图检查与分析.结果 30例患者中仅5例出现脑电图异常,表现为后头部波幅弥漫降低,而所有病例ET检测均有异常,表现为脑功能欠佳,记忆力指标下降;多巴胺、乙酰胆碱、强兴奋介质谷氨酸类显著增高,同时伴有弥散性缺血、缺氧指标,提示脑状态偏向缺血、兴奋以及应激水平增高.结论抽动-秽语综合征患者脑ET均存在明显异常,与传统脑电图比较,ET对该综合征的诊断敏感性更高.     

Tolerability profile of aripiprazole in patients with Tourette syndrome

Over the last few years, aripiprazole has been proposed as a potentially useful medication for tics in patients with Tourette syndrome (TS). Aripiprazole has been associated with fewer adverse effects compared with other atypicals; however, little is known about its tolerability profile in the TS population. This study assessed the prevalence and characteristics of adverse effects resulting from the use of aripiprazole in a retrospective chart review of 29 patients with TS. Six patients (20.7%) discontinued aripiprazole because of the severity of specific adverse effects. The most commonly reported adverse effects were sedation (n?=?9, 30%) and sleep problems (n?=?5, 17%). In the majority of cases, adverse effects were not severe. There were no differences in demographic or clinical variables between the patients who did or did not experience adverse effects. The discontinuation rate of 20.7% suggests that aripiprazole is safe and reasonably well tolerated for use in TS. The prevalence of adverse effects appears to increase with treatment duration.     

Polyamidoamine dendrimers can improve the pulmonary absorption of insulin and calcitonin in rats

The absorption-enhancing effects of polyamidoamine (PAMAM) dendrimers with various generations (G0-G3) and concentrations [0.1%-1.0% (w/v)] on the pulmonary absorption of peptide and protein drugs were studied in rats. Insulin and calcitonin were chosen as models of peptide and protein drugs, and their pulmonary absorption with or without PAMAM dendrimers was examined by in vivo pulmonary absorption studies. PAMAM dendrimers significantly increased the pulmonary absorption of insulin and calcitonin in rats, and their absorption-enhancing effects were generation dependent. The rank order of absorption enhancement effect of these PAMAM dendrimers was G3 > G2 > G1 > G0. For the same generation, the absorption-enhancing effects of PAMAM dendrimers were shown to be concentration dependent. The toxicity of these PAMAM dendrimers in the lung tissues was evaluated by measuring the release of protein and the activities of lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF). The PAMAM dendrimers with various generations and concentrations did not significantly increase the release of protein and the activities of LDH in BALF, indicating that these dendrimers did not cause any membrane damage to the lung tissues. The zeta potentials of insulin and calcitonin solutions changed to positive by the addition of PAMAM dendrimers, and the degree of positive charge as determined by the zeta potentials was linearly correlated with the absorption-enhancing effects of the PAMAM dendrimers. This positive charge of the PAMAM dendrimers might be related to their absorption-enhancing mechanisms for improving the pulmonary absorption of insulin and calcitonin in rats. In conclusion, the PAMAM dendrimers are suitable absorption enhancers to improve the pulmonary absorption of insulin and calcitonin without any membrane damage to the respiratory tissues.     

Inhibition of head twitch response to quipazine in rats by chronic amitriptyline but not fluvoxamine or citalopram

Chronic (twice daily/14 days), but not acute, treatment with 10 mg/kg PO amitriptyline reduced the number of quipazine (5 mg/kg)-induced head twitches in rats, measured 2 h (but not 72 h) after the last administration of the drug. Similar treatment with fluvoxamine or citalopram, which are more potent and much more specific serotonin uptake inhibitors than amitriptyline, did not affect the quipazine-induced response. In acute experiments, fluvoxamine (10 mg/kg PO) and citalopram (10 mg/kg PO) potentiated the head twitch reaction induced by l-5-hydroxytryptophan (50 mg/kg IP) given together with Ro 4-4602 (25 mg/kg IP), a peripheral decarboxylase inhibitor. Amitriptyline (10 mg/kg PO) slightly decreased the number of l-5-hydroxytryptophan (5-HTP)-induced head twitches. Higher doses of amitriptyline (20–40 mg/kg PO) also inhibited the quipazine-induced head twitch reaction. The brain level of amitriptyline measured 0.5–24 h after the last oral administration of the chronic dose of 10 mg/kg was always much higher than that observed at the same time intervals after an acute oral dose of 20 or 40 mg/kg. The results obtained indicate that a postsynaptic rather then presynaptic mechanism is responsible for the development of subsensitivity of the central serotonin receptors in the course of chronic treatment with amitriptyline.The results were presented at the 8th Congress of the Polish Pharmacological Society, Warszawa, 26–28 September 1983 Offprint requests to: L Pawowski