选择性5-HT1A受体拮抗剂WAY-100635抑制帕金森病模型大鼠腹内侧前额叶皮质的神经活动

目的 腹内侧前额叶皮质在随意运动的起始和控制、情感以及认知中具有重要作用.然而,黑质-纹状体通路变性后腹内侧前额叶皮质的神经活动和5-HT1A受体的作用仍不清楚.本研究观察了6-羟基多巴胺(6-hydroxydopamine,6-OHDA)损毁黑质致密部(substantia nigra pars compacta,SNc)后大鼠腹内侧前额叶皮质神经活动的变化和体循环给予选择性5-HT1A受体拮抗剂WAY-100635后神经元活动的改变.方法 采用在体玻璃微电极细胞外记录方法,记录正常大鼠和SNc单侧损毁大鼠的腹内侧前额叶皮质神经元的活动.结果 6-OHDA损毁SNc大鼠的腹内侧前额叶皮质神经元放电频率显著增加,放电形式没有明显改变.体循环给予WAY-100635(0.1 mg/kg,i.v.)不改变正常大鼠腹内侧前额叶皮质神经元的平均放电频率和放电形式,而显著降低了SNc损毁大鼠前额叶皮质神经元的平均放电频率.结论 黑质-纹状体通路的变性可导致腹内侧前额叶皮质神经活动增强,5-HT1A受体拮抗剂WAY-100635可以抑制这种活动增强,提示可能存在腹内侧前额叶皮质5-HT1A受体功能失调.     

腺苷A_(2A)受体拮抗剂治疗帕金森病的实验研究近况

近年的实验研究发现腺苷Ａ_２Ａ受体拮抗剂具有治疗帕金森病的作用。本文就腺苷Ａ_２Ａ受体及其拮抗剂的特性,腺苷Ａ_２Ａ受体拮抗剂治疗帕金森病的研究作一综述。     

慢性应激模型大鼠脑内5-HT1A受体表达分析

目的 探讨慢性不可预见性轻度应激(CUMS)模型大鼠各脑区(海马、中缝核、前额叶及纹状体)5-HT1A受体表达及与旷场行为变化的关系;西酞普兰对5-HT1A受体表达的影响.方法 将24只雄性SD大鼠随机分为3组(n=8):A组为对照组;B组为CUMS应激组;C组为CUMS应激+西酞普兰用药组(每天腹腔注射西酞普兰水溶液2 ml,10mg/kg).实验为期6周,通过旷场试验评价大鼠行为,6周后处死大鼠获取脑组织,采用Real-Time PCR检测各脑区5-HT1A mRNA表达水平,并分析其与矿场行为的相关性.结果 B组海马5-HT1A mRNA表达较A组有增高趋势(P=0.05),其余各脑区5-HT1A mRNA表达均差异无统计学意义(P＞0.05).海马5-HT1AmRNA表达大鼠移动次数、转身次数呈正相关,与总不动时间呈负相关;中缝核、纹状体5-HT1A mR-NA表达与中心移动距离呈正相关,纹状体5-HT1A mRNA表达与中心停留时间呈正相关(P均＜0.05).结论 慢性应激可能会引起海马5-HT1A受体表达增高;抗抑郁剂西酞普兰对5-HT1A受体表达无影响.5-HT1A mRNA表达与旷场行为变化有相关性.     

色氨酸羟化酶1与5-羟色胺2A受体基因对抑郁症患者额叶情绪加工的影响

目的:分析色氨酸羟化酶1 (TPH1)基因A218C多态性、5-羟色胺(5-HT)2A受体基因(HTR2A) T102C多态性对抑郁症患者额叶情绪识别功能异常的影响. 方法:28例抑郁症患者(患者组)及34名性别、年龄、受教育年限相匹配的健康对照(对照组)均进行情绪识别任务态下功能磁共振扫描,并以聚合酶链式反应-限制...     

5-HT1A受体对双相呼气和吸气神经元电活动的调制

目的探讨5-HT1A受体对延髓脑片双相呼气神经元和吸气神经元电活动的影响。方法在新生大鼠延髓脑片上同步记录舌下神经根和双相呼气神经元／吸气神经元单位的放电活动，并在灌流的改良Kreb’s液中先后加以5-HT1A受体的特异性激动剂（＋／-）-8-hydroxy-2-（di-N-propylamino）tetralin hydrobromide（8-OH-DPAT）和特异性拮抗剂多次甲基多苯基多异氰酸酯[4-iodo-N-[2-[4-（methoxyphenyl）-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride]（PMPPI）观察对神经元单位放电的影响。结果给予5-HT1A受体激动剂8-OH-DPAT后，双相呼气神经元／吸气神经元的呼吸周期和呼气时程明显延长，积分幅度降低，单位放电峰频率显著性降低；给予特异性拮抗剂PMPPI后，对呼吸周期，呼气时程的作用相反，而积分幅度和单位放电峰频率无明显变化。结论5-HT1A受体可能通过影响双相呼气神经元的电活动参与了呼吸时相的转换，同时也可能介导了吸气神经元的抑制性突触输入。     

5-HT1A受体的作用及其临床意义

5-羟色胺再摄取抑制剂（SSRI）是近十余年临床广泛应用的抗抑郁剂,有疗效好、不良反应轻和服药简便等多方面的优点,但在应用过程中也有起效较慢的缺点,特别是在抑郁症状严重需尽快解除时更显得不足。随着神经生理学和药理学的研究进展,人们已经发现SSRI类抗抑郁药起效慢的部份原因,并找到使其加快起效和疗效加强的一些措施。众所周知SSRI类抗抑郁药主要作用于中枢神经系统的5-羟色胺（5-HT）系统,抑制突触前膜对5-HT的再摄取、提高突触间隙的5-HT浓度是其主要药理作用机制。但抑郁症状的发生并非仅仅由于5-HT系统的功能不足所致,其中还包括去甲上腺素（NE）、多巴胺（DA）、γ-氨基丁酸（GABA）等系统的功能不足和／或紊乱,以及神经内分泌紊乱和受体后第二信使系统功能异常等多方面的因素。我们在本文中仅就5-HT1A受体的功能和5-HT1A激动剂和拮抗剂的药理作用和他们与SSRI疗效的关系进行综述。     

急性应激对大鼠脑内5-羟色胺1A受体mRNA表达的影响

目的 探讨急性应激对大鼠脑内5-羟色胺1A(5-HT1A)受体mRNA表达的影响。方法 将12只雄性Sprague-Dawley大鼠随机分为应激组和对照组,每组6只。根据5-HT1A受体互补DNA(eDNA)序列合成相应的特异性引物,用聚合酶链反应(PCR)法观察强迫游泳应激后3 h大鼠海马、下丘脑和中脑5-HT1A受体mRNA表达,并测定各脑区阳性电泳条带密度与β肌动蛋白(β-actin)密度的百分比。结果 应激后3 h,大鼠下丘脑5-HT1A受体mRNA表达相对水平为(64.3±6.7)％,显著低于对照组(78.9±8.7)％(t=3.263.P<0.05);海马、中脑5-HT1A受体mRNA表达相对水平分别为41.5％±7.1％、37.4％±5.6％,均分别显著低于对照组64.8％±9.6％、63.9％±6.3％(t分别为4.782、7.701,P均<0.01)。结论 急性应激后大鼠海马、下丘脑和中脑5-HT1A受体mRNA的表达降低。     

脑卒中后抑郁大鼠海马齿状回5-羟色胺1A受体的表达

目的 观察脑卒中后抑郁(PSD)大鼠海马齿状回5-羟色胺1A(5-HT1A)受体的表达.方法 将SD雄性大鼠分为正常对照组、卒中组、应激抑郁对照组和PSD组,每组6只.应用左侧大脑中动脉阻塞(MCAO)联合不可预见的慢性温和应激(CMS)刺激及孤养法建立PSD大鼠模型,采用荧光实时定量聚合酶链反应和Western印迹法检测并比较各组大鼠CMS第19天和第28天齿状回5-HT1A受体(mRNA)和蛋白表达水平.结果 (1)CMS第19天,PSD组5-HT1A受体mRNA表达(O.012±0.001)低于正常对照组(0.361±0.010)和卒中组(0.039±0.002;P＜0.001);其5-HT1A受体蛋白表达(0.400±0.030)低于正常组(1.320±0.060)和卒中组(0.610±0.060;均P＜0.001).(2)CMS第28天,PSD组5-HT1A受体mRNA(0.013±0.001)低于正常对照组(0.336±0.011)、卒中组(0.063±0.006;均P＜0.001);其5-HT1A受体蛋白表达(0.080±0.020)低于正常组(0.620 ±0.030)、卒中组(0.260±0.040)和应激抑郁组(0.320±0.020;均P＜0.001).结论 PsD大鼠海马齿状回5-HT1A受体表达水平降低,此改变可能是PSD发病的分子机制之一.     

5-羟色胺1A受体基因C(-1019)G多态性与精神分裂症的关联分析

目的:探讨云南地区汉族人群中5-羟色胺1A(5-HT1A)受体基因C(-1019)G多态性与精神分裂症的关联,及其对症状组成、前额叶执行功能的可能影响. 方法:应用阳性与阴性症状量表(PANSS)、简明精神病评定量表(BPRS)、外显攻击量表(OAS)等评定患者症状,威斯康星卡片分类测验(WCST)评定精神分裂症和正常人前额叶执行功能.142例精神分裂症患者和84名正常对照分别用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法进行基因分型. 结果:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性在精神分裂症和正常人之间的各量表分差异有显著性(P=0.001).C(-1019)G多态性对PANSS中因子被动淡漠性社会退缩(N4)(P=0.010)、言语缺乏主动性和流畅性(N6)(P=0.004)、阴性症状总分(NT)(P=0.013)、紧张(G4)(P=0.005)、自发社交回避(G16)(P=0.013),以及BPRS中的因子4激活性(P=0.026)等条目得分的形成影响有显著性.C(-1019)G多态性与WCST各条目不相关. 结论:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性与精神分裂症显著相关,对精神分裂症症状组成可能起一定作用,但与WCST反映的前额叶执行功能状态并无显著相关.     

5-羟色胺1A受体激动剂8-OH-DPAT对癫痫合并抑郁神经发生的研究

目的探讨5-羟色胺1A(5-HT1A)受体与匹罗卡品诱导的癫痫大鼠合并抑郁海马齿状回神经发生的关系。方法从匹罗卡品诱导的慢性自发性颞叶癫痫大鼠中筛选出合并抑郁的大鼠3 2只,随机分成模型组、卡马西平(CBZ)组、CBZ+8-OH-DPAT低剂量(0.1 mg/kg)组、CBZ+8-OH-DPAT高剂量(1.0 mg/kg)组,每组8只。对照组8只,注射生理盐水(1 0 m l/kg)。药物干预后,制备大鼠脑片,利用免疫组织化学方法检测大鼠的神经发生。结果模型组海马齿状回神经发生较对照组明显增多,差异有统计学意义(P<0.0 5)。CBZ组、CBZ+8-OH-DPAT低剂量组、CBZ+8-OH-DPAT高剂量组较模型组神经发生明显增多,差异有统计学意义(P<0.0 5)。CBZ+8-OH-DPAT高剂量组较CBZ组、CBZ+8-OH-DPAT低剂量组神经发生明显增多,差异有统计学意义(P<0.0 5)。但CBZ组与CBZ+8-OH-DPAT低剂量组比较神经发生的差异没有统计学意义(P>0.0 5)。结论高剂量的5-HT1A受体激动剂8-OH-DPAT在实验的过程中能够增加癫痫合并抑郁大鼠的神经发生。     

5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex

The present study investigated the neurochemical effects of the selective 5-HT(6) receptor antagonist SB-271046 in the rat medial prefrontal cortex (mPFC). The effect of SB-271046 on extracellular levels of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the mPFC was examined using in vivo microdialysis in the freely moving rat. SB-271046 (10 mg/kg, p.o.) produced a significant increase in extracellular levels of both DA and NE without altering 5-HT neurotransmission. These results further support the rationale for the use of 5-HT(6) receptor antagonists in the treatment of cognitive dysfunction associated with psychiatric diseases.     

Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [H]WAY-100635 and [C]WAY-100635

The distribution of 5-HT_1A receptors was examined in the post-mortem human brain using whole hemisphere autoradiography and the selective 5-HT_1A receptor antagonist [³H]WAY-100635 ([O-methyl-³H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride). The autoradiograms showed very dense binding to hippocampus, raphe nuclei and neocortex. The labeling in neocortex was slightly lower than in the hippocampus and was mainly at superficial layers, although a faintly labeled band could be seen in deeper neocortical layers. Other regions, such as the amygdala, septum and claustrum, showed low densities of [³H]WAY-100635 binding, reflecting low densities of 5-HT_1A receptors. The labeling was very low in basal ganglia, such as nucleus caudatus and putamen, in cerebellum or in structures of the brain stem except in the raphe nuclei. The labeling of human 5-HT_1A receptors with [³H]WAY-100635 was antagonized by the addition of the 5-HT_1A receptor ligands, 5-HT, buspirone, pindolol or 8-OH-DPAT (10 μM), leaving a very low background of non-specific binding. Saturation analysis of semiquantitative data from several human regions indicated that [³H]WAY-100635 has a K_d of approximately 2.5 nM. The selective labeling of 5-HT_1A receptors with [³H]WAY-100635 clearly show that this compound is useful for further studies of the human 5-HT_1A receptor subtype in vitro. [¹¹C]WAY-100635 is used for the characterization of 5-HT_1A receptors with positron emission tomography (PET). WAY-100635 was also radiolabeled with the short-lived positron-emitting radionuclide carbon-11 (t_1/2=20 min) and used for in vitro autoradiography on human whole hemisphere cryosections. [¹¹C]WAY-100635 gave images qualitatively similar to those of [³H]WAY-100635, although with a lower resolution. Thus, the hippocampal formation was densely labeled, with lower density in the neocortex. Buspirone, pindolol or 8-OH-DPAT (10 μM), blocked all binding of [¹¹C]WAY-100635. The in vitro autoradiography of the distribution of 5-HT_1A receptors obtained with radiolabeled WAY-100635 provide detailed qualitative and quantitative information on the distribution of 5-HT_1A-receptors in the human brain. Moreover, the studies give reference information for the interpretation of previous initial results at much lower resolution in humans with PET and [¹¹C]WAY-100635. These data provide a strong basis for expecting [¹¹C]WAY-100635 to behave as a highly selective radioligand in vivo.     

Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex

The ventral portion of the medial prefrontal cortex (vMPFC) is involved in the modulation of the parasympathetic component of the baroreflex. In the present study, we verified the effect of blockade of vMPFC glutamatergic receptors and nitric oxide synthases (NOS) on the parasympathetic component of baroreflex in awake rats. Bilateral microinjection of the non-selective ionotropic glutamate antagonist kynurenic acid (KYN) into the vMPFC caused a shift of the threshold of reflex bradycardia toward higher pressures in response to increases in mean arterial pressure (MAP) caused by intravenous infusion of phenylephrine, thus indicating a tonic facilitatory influence action of vMPFC glutamate receptors on the parasympathetic component of the baroreflex. The effect of blockade of vMPFC-NMDA receptors by AP7 was similar to that observed after KYN, suggesting mediation via NMDA receptors. Pretreatment with the NOS inhibitor L-NAME or the specific neural NOS (nNOS) N(omega)-propyl-l-arginine microinjected in the vMPFC caused a shift of the reflex threshold toward higher pressures that was similar to that observed after blockade of NMDA receptors, thus indicating participation of the NO/NMDA-receptor pathway in the vMPFC modulation of the parasympathetic component of the baroreflex. In conclusion, our data indicate that glutamatergic neurotransmission in the vMPFC has a tonic facilitatory influence on the parasympathetic component of the baroreflex. Because local treatment with either the nNOS inhibitor N(omega)-propyl-l-arginine or the specific NMDA antagonist AP7 had similar effects on the baroreflex, it is also suggested that this modulation involves an NMDA-NO interaction within the vMPFC.     

A pre- and postsynaptic modulatory action of 5-HT and the 5-HT2A, 2C receptor agonist DOB on NMDA-evoked responses in the rat medial prefrontal cortex.

Intracellular recordings were made from pyramidal neurons in layers V and VI of the rat medial prefrontal cortex in slice preparations to investigate the effect of the serotonin 5-HT2A,2C receptor agonist (-)-1-2,5-dimethoxy-4-bromophenol-2-aminopropane (DOB) and 5-hydroxytryptamine (5-HT) on N-methyl-D-aspartate (NMDA)-induced responses. Bath application of either DOB or 5-HT [in the presence of antagonists to 5-HT1A, 5-HT3 and gamma-aminobutytric acid (GABA) receptors] produced a concentration-dependent biphasic modulation of the NMDA responses. They facilitated and inhibited NMDA responses at low (相似文献   

Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease

The pedunculopontine nucleus (PPN) is a new deep brain stimulation (DBS) target for Parkinson's disease (PD), but little is known about PPN firing pattern alterations in PD. The anesthetized rat is a useful model for investigating the effects of dopamine loss on the transmission of oscillatory cortical activity through basal ganglia structures. After dopamine loss, synchronous oscillatory activity emerges in the subthalamic nucleus and substantia nigra pars reticulata in phase with cortical slow oscillations. To investigate the impact of dopamine cell lesion-induced changes in basal ganglia output on activity in the PPN, this study examines PPN spike timing with reference to motor cortex (MCx) local field potential (LFP) activity in urethane- or ketamine-anesthetized rats. Seven to ten days after unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, spectral power in PPN spike trains and coherence between PPN spiking and PPN LFP activity increased in the  1 Hz range in urethane-anesthetized rats. PPN spike timing also changed from firing predominantly in phase with MCx slow oscillations in the intact urethane-anesthetized rat to firing predominantly antiphase to MCx oscillations in the hemi-parkinsonian rat. These changes were not observed in the ketamine-anesthetized preparation. These observations suggest that dopamine loss alters PPN spike timing by increasing inhibitory oscillatory input to the PPN from basal ganglia output nuclei, a phenomenon that may be relevant to motor dysfunction and PPN DBS efficacy in PD patients.     

Acute and chronic administration of the selective 5-HT1A receptor antagonist WAY-405 significantly alters the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

In this study, we examined the effect of the acute and chronic administration of WAY-405, a selective 5-HT(1A) receptor antagonist, on the number and firing pattern of spontaneously active substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine (DA) neurons in anesthetized rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of WAY-405 (5-640 microg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active A9 and A10 DA neurons. A single injection of 10 microg/kg of WAY-405 decreased the number of spontaneously active A10 DA neurons and the 100 microg/kg dose significantly decreased the number of spontaneously active A9 and A10 DA neurons compared to vehicle-treated animals. A single injection of 1, 10, or 100 microg/kg of WAY-405 significantly decreased the degree of bursting of A10 DA neurons. In contrast, 1 microg/kg i.p. of WAY-405 significantly increased the percent of A9 DA neurons exhibiting a bursting pattern. The repeated administration of 10 or 100 microg/kg i.p. of WAY-405 (21 days) significantly decreased the number of spontaneously active DA neurons in both the A9 and A10 compared to vehicle-treated animals and this decrease was not reversed by i.v. (+)-apomorphine. The repeated administration of WAY-405 significantly altered the firing pattern of DA neurons, particularly those in the A10 area. Overall, these results indicate that the antagonism of the 5-HT(1A) receptor significantly alters the activity of midbrain DA neurons in anesthetized rats.     

Cerebral blood flow in the ventromedial prefrontal cortex correlates with treatment response to low-frequency right prefrontal repetitive transcranial magnetic stimulation in the treatment of depression

Aims: Low‐frequency right prefrontal repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression, and its antidepressant effects have proven to correlate with decreases in cerebral blood flow (CBF) in the orbitofrontal cortex and subgenual cingulate cortex. However, a predictor of treatment response to low‐frequency right prefrontal rTMS in depression has not been identified yet. The aim of this study was to estimate regional CBF in the frontal regions and investigate the correlation with treatment response to low‐frequency right prefrontal rTMS in depression. Methods: We examined 26 depressed patients for the correlation between treatment response to rTMS and regional CBF in the frontal regions, by analyzing their brain scans with ^99mTc‐ethyl cysteinate dimer before rTMS treatment. CBF in 16 brain regions was estimated using fully automated region of interest analysis software. Two principal components were extracted from CBF in 16 brain regions by factor analysis with maximum likelihood method and Promax rotation with Kaiser normalization. Results: Sixteen brain regions were divided into two groups: dorsolateral prefrontal cortex (superior frontal, medial frontal, middle frontal, and inferior frontal regions) and ventromedial prefrontal cortex (anterior cingulate, subcallosal, orbital, and rectal regions). Treatment response to rTMS was not correlated with CBF in the dorsolateral prefrontal cortex, but it was correlated with CBF in the ventromedial prefrontal cortex. Conclusion: These findings suggest that CBF in the ventromedial prefrontal cortex may be a potential predictor of low‐frequency right prefrontal rTMS, and depressed patients with increased CBF in the ventromedial prefrontal cortex may show a better response.     

Attention and working memory: a dynamical model of neuronal activity in the prefrontal cortex

Cognitive behaviour requires complex context-dependent mapping between sensory stimuli and actions. The same stimulus can lead to different behaviours depending on the situation, or the same behaviour may be elicited by different cueing stimuli. Neurons in the primate prefrontal cortex show task-specific firing activity during working memory delay periods. These neurons provide a neural substrate for mapping stimulus and response in a flexible, context- or rule-dependent, fashion. We describe here an integrate-and-fire network model to explain and investigate the different types of working-memory-related neuronal activity observed. The model contains different populations (or pools) of neurons (as found neurophysiologically) in attractor networks which respond in the delay period to the stimulus object, the stimulus position ('sensory pools'), to combinations of the stimulus sensory properties (e.g. the object identity or object location) and the response ('intermediate pools'), and to the response required (left or right) ('premotor pools'). The pools are arranged hierarchically, are linked by associative synaptic connections, and have global inhibition through inhibitory interneurons to implement competition. It is shown that a biasing attentional input to define the current rule applied to the intermediate pools enables the system to select the correct response in what is a biased competition model of attention. The integrate-and-fire model not only produces realistic spiking dynamicals very similar to the neuronal data but also shows how dopamine could weaken and shorten the persistent neuronal activity in the delay period; and allows us to predict more response errors when dopamine is elevated because there is less different activity in the different pools of competing neurons, resulting in more conflict.