Cyclin D1/D2/D3在大鼠脑胶质瘤组织中的表达

目的 探讨cyclin D1/D2/D3在大鼠脑胶质瘤组织中的表达.方法 将体外培养的大鼠C6胶质瘤细胞(细胞数为3×105个)借助动物立体定向仪接种于Wistar大鼠左侧尾状核区,解剖标本,行组织病理学检查及GFAP、cyclin D1/D2/D3免疫组化检测.结果 cyclinD1/D2/D3均呈阳性表达.cyclin D1/D3主要在细胞胞核表达,cyclin D2主要在胞浆表达,部分在胞核表达,不同存活期荷瘤鼠瘤组织中cyclin D1/D2/D3表达量不同.结论 cyclinD1/D2/D3过分表达参与调节大鼠脑胶质瘤增殖.荷瘤鼠生存期与cyclin D家族蛋白的表达呈负相关关系.     

125Ⅰ诱导大鼠脑内胶质瘤凋亡实验研究

目的研究125Ⅰ诱导人脑胶质瘤细胞系SHG-44体内外凋亡的可能性及其机制.方法体外培养SHG-44细胞,采用流式细胞仪法检测125Ⅰ诱导SHG-44细胞凋亡及对细胞周期影响,采用立体定向的方法建立大鼠脑内人胶质瘤模型,1周后经MRI检测后,于肿瘤区接种125Ⅰ,2周后复查MRI检测肿瘤大小,3周后处死大鼠,取对照组及肿瘤周边组织及肿瘤组织行Bcl-2、p53免疫组织化学染色.结果SHG-44细胞接种1周,MRI示脑内形成实体瘤;125I可抑制肿瘤生长,诱导细胞凋亡,延长荷瘤鼠生长周期,抑制Bcl-2基因表达,促进p53蛋白表达.结论125Ⅰ具有体内、外抑制SHG-44细胞增殖,诱导凋亡的作用;其诱导凋亡机制可能与抑制Bcl-2蛋白表达,促进p53蛋白表达有关.     

白细胞介素24对大鼠脑胶质瘤细胞Survivin表达的影响

目的探讨白细胞介素24(IL-24)基因对荷瘤大鼠脑胶质瘤细胞Survivin表达的影响。方法 48只SD大鼠随机分为实验组和对照组,每组24只,分别接种IL-24/C6细胞(转染IL-24基因的C6鼠脑胶质瘤细胞)和C6鼠脑胶质瘤细胞。接种21 d后,采用RT-PCR、Western blot和免疫组化方法检测两组大鼠脑肿瘤组织中Survivin mRNA和蛋白的表达,采用流式细胞学检测肿瘤细胞凋亡率。结果 RT-PCR检测显示:实验组大鼠脑肿瘤组织中Survivin mRNA表达水平明显低于对照组(P<0.01)。Western blot及免疫组化法检测显示:实验组大鼠脑肿瘤组织中Survivin的蛋白水平明显低于对照组(P<0.01)。流式细胞学结果显示:实验组细胞凋亡率显著高于对照组(P<0.01)。结论 IL-24可抑制大鼠胶质瘤中Survivin mRNA和蛋白的表达,促进细胞凋亡,抑制肿瘤生长。     

~(125)I诱导大鼠脑内胶质瘤凋亡实验研究

目的研究125I诱导人脑胶质瘤细胞系SHG-44体内外凋亡的可能性及其机制。方法体外培养SHG-44细胞,采用流式细胞仪法检测125I诱导SHG-44细胞凋亡及对细胞周期影响,采用立体定向的方法建立大鼠脑内人胶质瘤模型,1周后经MRI检测后,于肿瘤区接种125I,2周后复查MRI检测肿瘤大小,3周后处死大鼠,取对照组及肿瘤周边组织及肿瘤组织行Bcl-2、p53免疫组织化学染色。结果SHG-44细胞接种1周,MRI示脑内形成实体瘤;125I可抑制肿瘤生长,诱导细胞凋亡,延长荷瘤鼠生长周期,抑制Bcl-2基因表达,促进p53蛋白表达。结论125I具有体内、外抑制SHG-44细胞增殖,诱导凋亡的作用;其诱导凋亡机制可能与抑制Bcl-2蛋白表达,促进p53蛋白表达有关。     

胶质瘤组织芯片cathepsin D的表达和临床意义

目的 构建高通量组织微阵列/组织芯片(high-throughput tissue microarray/tissue chip),分析组织蛋白酶D(cathepsin D,Cath D)在胶质瘤中的表达,并分析其临床意义.方法 选取胶质瘤病理标本300例制成组织芯片,应用免疫组织化学方法研究Cath D在胶质瘤中的表达.结果 Cath D在病理分级Ⅰ～Ⅱ、Ⅲ～Ⅳ级星形细胞肿瘤中表达阳性率分别为56.84%、81.89%,统计学有显著差异,并且阳性程度的表达有显著差异,星形细胞肿瘤与正常组织对照(31.5%)的表达率均有差异.Cath D在临床分级Ⅱ、Ⅲ级的室管膜细胞肿瘤中表达的阳性率及阳性程度没有显著差异,室管膜细胞肿瘤与对照正常组织(31.5%)的表达有差异.Cath D在临床分级Ⅱ、Ⅲ级的少枝胶质细胞肿瘤中的表达阳性率分别为66.66%、86.95%.阳性程度有显著差异,少枝胶质细胞肿瘤与同一患者正常组织对照(31.5%)的表达有差异.结论 Cath D表达与星形细胞肿瘤、少枝胶质细胞肿瘤的病理分级呈正相关,可以作为判断高级别星形细胞肿瘤及高级别少枝胶质细胞肿瘤的分子标记.     

胶质瘤PTEN和细胞周期蛋白D1表达及其意义

目的　探讨胶质瘤组织中PTEN和细胞周期蛋白D1(CyclinD1)表达的意义。 方法　应用免疫组化结合计算机图像分析方法检测PTEN和CyclinD1蛋白在 80例胶质瘤的表达及其相关关系。结果　PTEN阳性率为 6 3.8% (5 1/ 80 ) ,低分级胶质瘤 (I～II)阳性率显著高于III级和IV级 (P<0 .0 1) ;胶质瘤不同病理分级间CyclinD1蛋白表达存在显著性差异 (P <0 .0 1)。胶质瘤细胞CyclinD1与PTEN蛋白表达呈显著性负相关关系 (r=- 0 .5 4 3,P <0 .0 1)。结论　PTEN蛋白表达可能在胶质瘤细胞周期调节和细胞增殖中发挥重要作用     

骨髓基质干细胞移植对大鼠胶质瘤局部微环境的影响

目的:探讨骨髓基质干细胞(BMSCs)移植对脑胶质瘤模型大鼠(荷瘤大鼠)胶质瘤的影响。方法:观察BMSCs培养上清液对C6胶质瘤细胞增殖活性、细胞周期的影响。观察脑内移植BMSCs对胶质瘤核增殖抗原(PCNA)表达阳性率、脑内胶质瘤微血管计数的影响及荷瘤鼠生存期的改变。结果:BMSCs培养上清液对胶质瘤细胞增殖没有明显的影响;BMSCs可抑制肿瘤边缘及卫星灶的肿瘤增殖,对肿瘤内部的细胞增殖没有明显影响。移植BMSCs后肿瘤边缘及卫星灶的微血管计数未见明显改变。移植BMSCs后的荷瘤大鼠脑内胶质瘤水肿有所减轻。结论:BMSCs移植可轻度抑制荷瘤鼠脑内胶质瘤细胞的增殖。     

胶质瘤中cyclinD1和p57/Kip2蛋白的表达及意义

目的探讨p57/Kip2和细胞周期素cyclinD1在人脑胶质瘤中的表达及意义。方法收集54例胶质瘤和12例正常脑组织标本,应用免疫组化方法检测胶质瘤组织及其正常脑组织中p57/Kip2和cyclinD1蛋白的表达水平。结果免疫组化方法结果显示胶质瘤组织中cyclinD1蛋白水平显著高于正常脑组织,而p57/Kip2的表达水平显著低于正常脑组织,且Pearson相关系数检验提示,胶质瘤组织中p57/Kip2和cyclinD1蛋白的表达水平呈负相关(P0.01)。结论 p57/Kip2胶质瘤组织中表达显著下调,cyclinD1蛋白在胶质瘤组织中异常高表达,且二者表达水平呈显著负相关(r=-0.782,P0.01)。     

^125I诱导大鼠脑内胶质瘤凋亡实验研究

目的 研究^125I诱导人脑胶质瘤细胞系SHG-44体内外凋亡的可能性及其机制。方法 体外培养SHG-44细胞，采用流式细胞仪法检测^125I诱导SHG-44细胞凋亡及对细胞周期影响，采用立体定向的方法建立大鼠脑内人胶质瘤模型．1周后经MRI检测后．于肿瘤区接种^125I，2周后复查MRI检测肿瘤大小，3周后处死大鼠，取对照组及肿瘤周边组织及肿瘤组织行Bcl-2、p53免疫组织化学染色。结果 SHG-44细胞接种1周，MRI示脑内形成实体瘤；^125I可抑制肿瘤生长，诱导细胞凋亡。延长荷瘤鼠生长周期。抑制Bcl-2基因表达，促进p53蛋白表达。结论^125I具有体内、外抑制SHG-44细胞增殖，诱导凋亡的作用：其诱导凋亡机制可能与抑制Bcl-2蛋白表达，促进p53蛋白表达有关。     

人羊膜间充质干细胞移植对荷瘤鼠C6胶质瘤生长的抑制

背景：实验室前期课题成果显示，脐血或羊膜间充质干细胞具有亲肿瘤及抑瘤特性。 目的：探讨人羊膜间充质干细胞对C6胶质瘤细胞生长的抑制作用。 设计、时间及地点：细胞学体内对照观察，于2008-06/09在郑州大学微生物与免疫教研室完成。 材料：胎盘来源于郑州大学一附院妇产科健康剖宫产产妇，C6胶质瘤细胞株由北京神经外科研究所惠赠，10只BALR/c裸鼠由上海斯莱克实验动物有限责任公司提供。 方法：无菌条件下取胎盘，分离部分羊膜，体外分离培养人羊膜间充质干细胞，传至第3代用于实验。10只裸鼠背部双侧皮下注射含3×106个C6胶质瘤细胞的DMEM/F12培养基，建立双侧荷瘤鼠模型。成功造模后，模型对照组于裸鼠左侧皮下注射DMEM/F12培养基50μL，细胞移植组于同一裸鼠右侧皮下注射含2×106个羊膜间充质干细胞的等量DMEM/F12培养基。 主要观察指标：肿瘤生长情况，周围组织浸润及新生血管形成等病理学观察，免疫组化法检测肿瘤中细胞周期素D1的表达。 结果：细胞移植后14，21 d，细胞移植组肿块体积明显小于模型对照组（F=54.127，P < 0.05）。模型对照组瘤体呈结节状，部分肿瘤组织中心有坏死现象，内部有新生血管形成，肌层及皮肤浸润较明显，已达腹膜；细胞移植组瘤体分叶较少，无新生血管形成，仅有局部的皮肤浸润，未见肌层浸润。模型对照组细胞周期素D1蛋白呈阳性表达，而细胞移植组表达阳性率较低。 结论：人羊膜间充质干细胞可明显抑制荷瘤鼠C6胶质瘤细胞的生长，同时可抑制细胞周期素D1蛋白的异常表达。     

Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: Electrophysiological and behavioral studies

Many effects resulting from D₂ dopamine (DA) receptor stimulation are manifest only when D₁ DA receptors are stimulated by endogenous DA. When D₁ receptor stimulation is enhanced by administration of selective D₁ receptor agonists, the functional effects of selective D₂ agonists are markedly increased. These qualitative and quantitative forms of D₁/D₂ DA receptor synergism are abolished by chronic DA depletion when both D₁ and D₂ DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D₁ and D₂ renaptnr supersensitivity, induced by repeated administration of selective D₁ or D₂ receptor antagonists, on the synergistic relationships between D₁ and D₂ receptors. Daily administration of the selective D₂ antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D₂ agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D₁ agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D₂ receptors from the necessity of D₁ receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (sterotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D₁ receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D₁ receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390-pretreated rats. When such Dl-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D₁-sensitized rats are due to a heterologous sensitization of D₂ receptors rather than to enhanced enabling resulting from supersensitive D₁ receptors. It is suggested that supersensitivity of either D₁ or D₂ receptors can lead to an uncoupling of normal qualitative and quantitative D₁/D₂ synergisms and that the heterologous regulation of D₂ receptor sensitivity by D₁ receptors may be related to uncoupling of functional D₁/D₂ synergisms.     

一种基于2D/3D配准的脊柱术中校正方法

背景：脊柱术前三维影像有助于诊断和治疗，术中患者体位变化将引起脊柱形态改变，致使术前影像不能反映术中实际情况，无法确保手术的顺利实施。 目的：利用脊髓手术中影像校正术前脊柱模型形态。 方法：实验提出了一种基于2D/3D配准的脊柱术中校正方法，借助数字影像重建技术完成术前X射线图像与CT体数据的2D/3D配准，进一步完成术中、术前X射线图像中独立椎段的特征匹配，利用上述配准结果实现术前脊柱CT模型的术中快速校正。 结果与结论：采用附有标记的颈椎标本进行实验，校正后可基本消除术前脊柱模型与术中形态的偏差，其误差可控制在1 mm以内，能够满足医学临床要求。     

Alterations in D1/D2 synergism may account for enhanced stereotypy and reduced climbing in mice lacking dopamine D2L receptor

Concurrent activation of dopamine D1 and D2 receptors (D1 and D2) is required for the expression of certain dopamine (DA)-mediated responses, such as climbing and stereotyped behaviors. Such interactions between D1 and D2 (i.e. D1/D2 synergism) represent an important aspect of dopaminergic function and plasticity. The D2 receptor exists in two isoforms: D2L and D2S. We have generated mice that selectively lack D2L (D2L-/-). Here we showed that treatment with the indirect DA agonist amphetamine, the direct DA agonist apomorphine, or combination of D1 and D2 agonists elicited intense climbing in wild type mice (which express predominantly D2L in the striatum), but this behavior was absent or reduced in D2L-/- mice. On the other hand, apomorphine, the D2 agonist quinpirole, or combination of quinpirole and the D1 agonist SKF 81297 induced more stereotyped behavior such as biting or head movements in D2L-/- mice (which express only D2S) than in wild type mice. The D1 receptor functioned normally in D2L-/- mice. Taken together, these results suggest that D2L and D1 interactions may play a greater role in DA agonist-induced climbing, whereas D2S and D1 interactions may have a larger impact on DA agonist-induced stereotypy (and possibly psychosis). DA agonists, which are clinically used to treat Parkinson's disease and attention-deficit hyperactivity disorder (ADHD), are known to induce psychotic side effects. Thus, our findings may provide novel insights for designing anti-parkinsonian, anti-ADHD and antipsychotic drugs with greater therapeutic efficacy and fewer side effects.     

Dopamine D1/D5 receptor signaling regulates synaptic cooperation and competition in hippocampal CA1 pyramidal neurons via sustained ERK1/2 activation

Synaptic cooperation and competition are important components of synaptic plasticity that tune synapses for the formation of associative long‐term plasticity, a cellular correlate of associative long‐term memory. We have recently reported that coincidental activation of weak synapses within the vicinity of potentiated synapses will alter the cooperative state of synapses to a competitive state thus leading to the slow decay of long‐term plasticity, but the molecular mechanism underlying this is still unknown. Here, using acute hippocampal slices of rats, we have examined how increasing extracellular dopamine concentrations interact and/or affect electrically induced long‐term potentiation (LTP) in the neighboring synapses. We demonstrate that D1/D5‐receptor‐mediated potentiation at the CA1 Schaffer collateral synapses differentially regulates synaptic co‐operation and competition. Further investigating the molecular players involved, we reveal an important role for extracellular signal‐regulated kinases‐1 and 2 (ERK1/2) as signal integrators and dose‐sensors. Interestingly, a sustained activation of ERK1/2 pathway seems to be involved in the differential regulation of synaptic associativity. The concentration‐dependent effects of the modulatory transmitter, as demonstrated for dopaminergic signaling in the present study, might offer additional computational power by fine tuning synaptic associativity processes for establishing long‐term associative memory in neural networks. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain

We studied in healthy humans the contribution of cerebral dopamine D2/D3 receptors to individual differences in response characteristics to painful stimulation. Positron emission tomography was used to measure the dopamine D2/D3 binding potential (D2/D3 BP) with [(11)C]raclopride in the striatum (n = 8) and with [(11)C]FLB 457 in the extrastriatal regions (n = 11). Sensitivity to cutaneous heat pain was assessed by a traditional threshold method and by an analysis based on the signal detection theory which allows the separation of an individual subject's discriminative capacity from the response criterion, i.e. the area under the receiver operating characteristic curve provides a measure of the sensory discriminability (sensory factor) and the response criterion gives an estimate of the subject's response bias or attitude (nonsensory factor). The pain threshold and response criterion were inversely correlated with the D2/D3 BP in the right putamen, whereas the discriminative capacity was not significantly correlated with the D2/D3 BP in any brain region. The correlation of the D2/D3 BP in the putamen with the pain threshold and the subject's response criterion may rather be explained by a dopaminergic effect on nonsensory factors determining the subject's attitude towards pain than by a dopaminergic effect on the subject's discriminative capacity. Alternatively, striatal dopamine D2/D3 receptors could control a modulatory pathway producing a parallel shift in the stimulus-response function for sensory signals, mimicking a change in the subject's response criterion.     

Repeated trimipramine induces dopamine D2/D3 and α1-adrenergic up-regulation

Summary. Trimipramine (TRI), which shows a clinical antidepressant activity, is chemically related to imipramine but does not inhibit the reuptake of noradrenaline and 5-hydroxytryptamine, nor does it induce β-adrenergic down-regulation. The mechanism of its antidepressant activity is still unknown. The aim of the present study was to find out whether TRI given repeatedly was able to induce adaptive changes in the dopaminergic and α₁-adrenergic systems, demonstrated by us previously for various antidepressants. TRI was given to male Wistar rats and male Albino Swiss mice perorally twice daily for 14 days. In the acute experiment TRI (given i.p.) does not antagonize the reserpine hypothermia in mice and does not potentiate the 5-hydroxytryptophan head twitches in rats. TRI given repeatedly to rats increases the locomotor hyperactivity induced by d-amphetamine, quinpirole and (±)-7-hydroxy-dipropylo-aminotetralin (dopamine D₂ and D₃ effects). The stereotypies induced by d-amphetamine or apomorphine are not potentiated by TRI. It increases the behaviour stimulation evoked by phenylephrine (given intraventricularly) in rats, evaluated in the open field test as well as the aggressiveness evoked by clonidine in mice, both these effects being mediated by an α₁-adrenergic receptor. It may be concluded that, like other tricyclic antidepressants studied previously, TRI given repeatedly increases the responsiveness of brain dopamine D₂ and D₃ (locomotor activity but not stereotypy) as well as α₁-adrenergic receptors to their agonists. A question arises whether the re-uptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity. Accepted January 21, 1998; received November 3, 1997     

局灶性脑缺血对细胞周期蛋白D1/CDK4基因表达的影响

目的观察脑缺血后细胞周期蛋白（cyclin）D1和它的酶CDK4基因表达，以及这种表达的改变是否影响神经细胞凋亡。方法成年雄性SD大鼠32只随机分为假手术组（n=4）和实验组（n=28），实验组再进一步分为7个亚组（再灌注2h，6h，12h，1d，3d，7d和14d，每组n=4）。应用线栓法建立SD大鼠大脑中动脉阻塞／再灌注模型．TUNEL法检测神经细胞凋亡。原位杂交检测cyclinD1和CDK4mRNA的表达。结果CyclinD1mRNA和CDK4mRNA的表达与凋亡细胞的区域基本相同。再灌注2h脑组织即开始出现神经细胞凋亡，并于1d分别在皮层区和纹状体区达高峰（分别为72．80±4．66和87．75±0．85）。神经细胞cyclinD1mRNA和CDK4mRNA的表达分别于再灌注2h和6h开始逐渐增强，并于12h和1d达高峰（皮质区分别为94．50±2．75和85．75±3．73，纹状体区分别为88．25±5．06和89．80±2．93）。结论CyclinD1和CDK4选择性地在形态学完整或已经有改变的缺血侧神经元和少突胶质细胞内表达。CyclinD1／CD1（4mRNA表达可能是诱导细胞凋亡的重要因素之一。     

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.     

Antiparkinsonian effects of the novel D3/D2 dopamine receptor agonist, S32504, in MPTP-lesioned marmosets: Mediation by D2, not D3, dopamine receptors.

L-dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D3/D2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D2 vs. D3 receptors, an issue we addressed with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned nonhuman primate model of Parkinson's disease. In L-dopa-primed animals, S32504 (0.16-2.5 mg/kg p.o.) dose-dependently enhanced locomotor activity. This action was abolished by the D2 antagonist, L741,626 (2.5 mg/kg), but potentiated by the D3 antagonist, S33084 (0.63 mg/kg). Both antagonists were inactive alone. In drug-naive animals, a maximally effective dose of S32504 (2.5 mg/kg p.o.) displayed pronounced antiparkinsonian properties from the third day of administration, and its actions were expressed rapidly and durably. Thus, on day 33, antiparkinsonian properties of S32504 were apparent within 5 minutes and present for > 4 hours. Moreover, they were associated with neither wearing off nor significant dyskinesia. In conclusion, the novel D3/D2 agonist S32504 may offer advantages over L-dopa in the treatment of newly diagnosed parkinsonian patients. Its actions are expressed primarily by activation of D2, not D3, receptors.