司来吉兰治疗帕金森病新进展

司来吉兰是一种选择性不可逆的单胺氧化酶B抑制剂，目前不仅作为帕金森病（PD）早期的一线治疗药物，而且作为PD晚期的辅助治疗药物被广泛运用。司来吉兰治疗PD具有独特的优势，能够改善早期PD的症状和体征，延缓其进程，保护神经元；对晚期PD辅助左旋多巴治疗也有较好的疗效。但其也有不良反应。本文介绍司来吉兰在临床应用的进展。     

盐酸司来吉兰治疗早期帕金森病的疗效观察

目的 观察司来吉兰治疗早期帕金森病（PD）的疗效和安全性。方法 采用随机空白对照法,将60例已用安坦、金刚烷胺、维生素E联合治疗的早期PD患者分为司来吉兰治疗组和空白对照组,前者在原用药物剂量不变的基础上添加盐酸司来吉兰片5mg/d,疗程8周。采用改良Webster评分评价药物疗效并观察不良反应。结果 司来吉兰组治疗后4周及8周时改良Webster评分较治疗前明显改善（均P〈0．01）,且明显低于空白对照组（均P〈0．05）;司来吉兰组总有效率为76．7％,明显优于空白对照组（P〈0．01）;未见明显不良反应。结论 司来吉兰是一种安全有效的早期PD治疗用药。     

司来吉兰添加治疗帕金森病临床疗效评价

目的：观察司来吉兰添加治疗帕金森病的临床疗效及安全性。方法：采用随机双盲安慰剂对照方法，在复方多巴治疗的基础上添加国产司来吉兰治疗40例帕金森病患，分为司来吉兰治疗组和安慰剂对照组，疗程8周。采用改良的Webster评分量表评估药物疗效并观察不良反应。结果：司来吉兰治疗组治疗前后自身对照Webster评分有明显改善（P＜0．05或P＜0．01），安慰剂对照组于治疗后第4，6周差异有显性意义（P＜0．05或P＜0．01），司来吉兰组疗效优于安慰剂组（P＜0．01），司来吉兰组患治疗的总有效率为80％，与安慰剂组（40％）比较差异有显性意义（P＜0．01）。司来吉兰组患药物不良反应轻微。结论：司来吉兰是一种安全有效 的抗帕金森病辅助药物。     

国产盐酸司来吉兰添加治疗原发性帕金森病

帕金森病 (Ｐａｋｉｎｓｏｎ’ｓｄｉｓｅａｓｅ ,ＰＤ)是常见的中枢神经系统退行性疾病。多发于中老年 ,65岁以上人群中患病率大约为 1%。Ｌ 多巴的替代疗法是目前治疗ＰＤ长期的主要手段 ,但应用多巴制剂治疗后必然出现疗效减退和多巴长期治疗并发症 ,如异动症(ｄｙｓｋｉｎｅｓｉａｓ)、“开关”现象、剂末效应等。内源性多巴胺减少 ;药物和疾病使多巴胺受体逐步变性。造成对多巴胺的不敏感可能是长期服用左旋多巴制剂后疗效减退的原因。或与长期应用多巴制剂后引起突触后受体功能的改变有关。因此必须继续寻找其他更好的疗法。尽管各种…     

司来吉兰联合复方多巴治疗帕金森病的疗效观察

目的观察司来吉兰联合复方多巴治疗帕金森病的疗效。方法选取我院神经内科治疗的90例帕金森病患者为研究对象,随机分为2组,对照组单用复方多巴治疗,观察组采用司来吉兰联合复方多巴治疗,服用12周后比较2组临床疗效、帕金森病统一评分量表(UPDRS)及改良Webster症状量表评分、非运动并发症发生率。结果观察组总有效率为88.89%,明显高于对照组的60%,差异有统计学意义(P0.05);观察组治疗后UPDRS评分及Webster评分较对均照组明显改善,差异有统计学意义(P0.05);观察组睡眠和疲劳、情绪与认知、知觉与幻觉、注意力与记忆力、心血管系统、胃肠道症状、泌尿系统症状、性功能等非运动并发症发生率明显低于对照组,差异有统计学意义(P0.05)。结论司来吉兰联合复方多巴治疗帕金森病效果显著,有利于肌强直、静止性震颤、姿势步态障碍、运动迟缓等症状改善,减少症状波动,降低非运动并发症,安全性较高,具有积极的临床意义。     

司来吉兰联合复方多巴治疗帕金森病临床观察

目的评价司来吉兰联合复方多巴(左旋多巴/苄丝肼或左旋多巴/卡比多巴控释片)治疗已有药效减退的中、晚期帕金森病患者的疗效和安全性。方法对38例服用复方多巴治疗已有药效减退的中、晚期帕金森病患者联合司来吉兰,连续服用8周。在加药前、后进行十大症状的Webster评分对比和常规实验室指标检测。结果 Webster评分显示10例有中度疗效,15例有轻度疗效,十大症状的各项评分比较,在加药前、后均差异有统计学意义(P<0.05)。6例有"开-关"现象的患者,加药后4例明显改善。不良反应主要为胃肠道反应,未发现其他严重不良反应。结论对于复方多巴治疗已有药效减退的帕金森病患者,联合司来吉兰是安全、有效的。     

司来吉兰联合复合多巴治疗帕金森病的有效性和安全性

目的 探讨司来吉兰联合复合多巴治疗帕金森病的疗效和安全性.方法 将89例帕金森病患者随机分为对照组(45例)和治疗组(44例),对照组患者采用复合多巴等药物治疗,治疗组患者加用司来吉兰治疗,6个月为1个观察周期.于用药前及用药后1、3、6个月采用PD统一评分量表(UPDRS)对两组患者进行疗效评定,并观察其不良反应.结果 治疗组患者治疗1个月时与治疗前相比,除UPDRSⅢ评分降低外(P＜0.01),UPDRSⅠ、Ⅱ、Ⅳ评分变化均无统计学差异(均P＞0.05);治疗3、6个月时与治疗前比较,其UPDRSⅠ～Ⅳ评分均下降(P＜0.01);治疗3、6个月时与治疗1个月时比较,UPDRS Ⅰ、Ⅲ、Ⅳ评分降低均降低(P＜0.01,P＜0.05);治疗6个月时与治疗3个月时相比,其UPDRS Ⅰ～Ⅳ评分均无统计学差异(P＞0.05).治疗3、6个月时,治疗组UPDRSⅠ～Ⅳ评分均明显低于对照组(P＜0.01,P＜0.05).观察期内,两组患者未出现严重不良反应.结论 司来吉兰联用复合多巴可有效改善帕金森病症状,且耐受性好,不良反应少.     

美多巴联合司来吉兰治疗帕金森病患者临床效果及安全性评价

目的探讨美多巴联合司来吉兰治疗帕金森病患者临床效果及其安全性评价。方法本研究病例来源于2014年8月至2015年8期间我院收治的原发性帕金森病患者86例,依据随机数字表法分为观察组43例与对照组43例。观察组采用美多巴联合司来吉兰治疗,对照组仅采用美多巴治疗。两组疗程均为3个月。结果观察组总有效率(86.05%)高于对照组(67.44%)(P0.05);两组Webster评分治疗后明显减少(P0.05);观察组Webster评分治疗后低于对照组(P0.05);两组MDRSPD评分治疗后明显减少(P0.05);观察组MDRSPD评分治疗后低于对照组(P0.05);两组均未见严重用药不良反应。结论美多巴联合司来吉兰治疗帕金森病患者临床效果显著,且安全可靠。     

左旋多巴对C17．2神经干细胞的毒性作用及司来吉兰的神经保护作用

目的　 探讨左旋多巴对C17.2神经干细胞的毒性作用和司来吉兰对其的拮抗作用。 方法　 采用MTT法检测不同剂量左旋多巴对C17.2神经干细胞的毒性作用 ,用Brdu标记检测左旋多巴对细胞增殖的影响 ,用透射电镜、Annexin V染色荧光显微镜和流式细胞仪检测细胞凋亡 ,用WesternBlot检测Caspase3及其活性片段 ;相同条件下同时检测司来吉兰的保护作用。结果　 MTT显示左旋多巴可使C17.2神经干细胞活性降低 ,与剂量相关 (P <0 .0 5 ) ,Brdu标记显示 2 0 0 μmol/L左旋多巴可使细胞增殖活力下降 ,与时间相关 (P <0 .0 5 ) ,作用 12及 2 4h后的透射电镜、Annexin V染色荧光显微镜和流式细胞仪可检测到凋亡细胞 ,WesternBlot显示Caspase 3表达量增加 ,并逐渐被切割成活性片段。司来吉兰能部分保护细胞免受左旋多巴的影响 (P <0 .0 5 ) ,并能部分抑制左旋多巴引起的细胞凋亡 (P <0 .0 5 )。 结论　 大剂量左旋多巴对C17.2神经干细胞具有毒性作用 ,呈剂量和时间依赖性。毒性剂量的左旋多巴可通过抑制DNA合成影响细胞增殖 ,并通过活化Caspases 3促进细胞凋亡 ,司来吉兰可部分拮抗上述作用。     

司来吉兰治疗嗜睡2例

我们用单胺氧化酶抑制剂司来吉兰治疗嗜睡,取得较好效果,报告如下。 1病例 例1,患者男,26岁。因白天发作性睡眠伴自言自语傻笑7年入院。7年来患者白天上课时睡觉,每次睡觉时间约30min左右,每天发作约10次,每次都能自己醒来,醒来后继续学习,行走时伴有自言自语傻笑。家族史阴性。体格检查正常。精神检查：意识清晰,定向完整,接触较为被动,情感协调,意志活动略减退,未查及幻觉、妄想等,但有傻笑。     

Ghrelin antagonizes MPTP-induced neurotoxicity to the dopaminergic neurons in mouse substantia nigra

Ghrelin, a stomach-derived hormone which induces growth hormone release and promotes positive energy balance, has been reported to inhibit cell apoptosis in endotheliocytes, osteoblasts and cardiocytes. Recent evidence has shown that ghrelin can also inhibit neuronal apoptosis of the hypothalamus and the hippocampus. However, little is known about the effects of ghrelin on the substantia nigra pars compacta (SNpc) neurons in which ghrelin's receptor, growth hormone secretagogue receptor (GHSR)-1a, is highly expressed. In the present study, we investigated whether ghrelin could protect nigral dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. We observed that ghrelin, acting through GHS-R 1a, inhibited MPTP-induced dopaminergic neuronal loss in the SNpc as well as dopamine depletion in the striatum. Ghrelin could also reverse the down-regulated the expression of Bcl-2, up-regulated the expression of Bax, and caspase-3 activation caused by MPTP. This study demonstrated that ghrelin might be a potential protector of dopaminergic neurons in a therapeutic strategy for Parkinson's disease.     

Selegiline in de novo parkinsonian patients: The French selegiline multicenter trial (FSMT)

The French selegiline multicenter trial was conducted in 1990 to test the possibility to improve disability of de novo parkinsonian patients (P. P.) during the first three months of treatment with selegiline (S) (10 mg/day) monotherapy. 93 P. P. were included in this double-blind, randomized, placebo controlled, clinical trial, in which 13 centers participated. Both parallel groups were followed up from inclusion (D0) to D30, D60 and D90. Drug efficacy was judged with Hoehn and Yahr (HY), Hamilton Depression Rating Scale (HDRS), Unified Parkinson's Disease Rating Scale (UPDRS), Schwab and England scores, decision to introduce levodopa and selfassessment. Biological and clinical parameters (cardio- vascular, weight, side-effects reports) were assessed for tolerability. 84 P. P. (38 P, 46 S) were evaluable for efficacy at D90.
When considering the main parameters, S appears superior to placebo: HY scores (p < 0.001), global UPDRS scores (p < 0.001) and UPDRS subscores: mental (p < 0.001), daily living activities (p < 0.01), motor activities (p < 0.01). Depressive scores (HDRS) are significantly improved only at D90 (p=0.005). Levodopa therapy was introduced in 45 % of the cases in S groups versus 18,4 % in P group. Global impression of efficacy was largely in favor of S; failure was noted in half of the cases in P group and only in 1/5th of the cases in S group. Side-effects were rare and minor.
S 10 mg/day monotherapy is statistically superior to placebo in improving de novo P. P. during the first three months treatment. Motor symptoms rapidly improve; mood is only modified after 3 months. S appears to be well tolerated. S may be considered as a good candidate for the initial treatment of P. P.     

MPTP-induced parkinsonism as a model for Parkinson's disease

Abstract– It is now well recognized that 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) can induce a syndrome in human and non-human primates similar to Parkinson's disease. This highly selective neurotoxin, which affects specific catecholaminergic nuclei in the brainstem, has provided an important new tool for the study of Parkinson's disease. In this article we review several specific areas related to current research on MPTP, including the question of disease progression, issues regarding the validity of the animal model induced by MPTP, the role of aging in regard to its neurotoxicity and Parkinson's disease, and new therapeutic strategies that have evolved from basic research with the compound. We conclude that both clinical and basic research stemming from the discovery of MPTP have provided valuable insights regarding both the cause and treatment of Parkinson's disease.     

The effects of acute loading with levodopa and levodopa with selegiline on blood pressure and plasma norepinephrine levels in chronic Parkinson's disease patients

OBJECTIVES: Contradictory possible cardiovascular side effects of selegiline have been reported. Therefore, we studied the effect of acute administration of selegiline with levodopa (LD) compared with LD alone, on blood pressure, pulse and norepinephrine (NE) plasma levels, during an orthostatic test on chronically treated Parkinson's disease patients (PDpts) and controls. MATERIALS AND METHODS: Twelve PDpts treated with LD (group D), 12 PDpts treated with selegiline and LD (group S) and eight volunteers (CTRL) underwent the orthostatic test. Patients repeated the test twice, before and after acute loading with 125 mg LD (group D) and 125 mg LD +5 mg selegiline (group S). RESULTS: Group S showed more episodes of postural hypotension (n = 10; two symptomatic) than group D (n = 4) and CTRL (n = 2), however not statistically significant. Plasma NE also rose significantly higher (P < 0.001) in group S. CONCLUSION: PD patients treated with selegiline showed more orthostatism and higher plasma NE after submission to the orthostatic test. These findings may be relevant to explain its deleterious effect.     

Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism: II. Effects of reward preference

The motor and cognitive symptoms of Parkinson's disease (PD) are well documented, but little is known about the functionality of motivational processes mediated by the limbic circuits of basal ganglia. The aim of this study was to test the ability of motivational processes to direct and to urge behaviour, in four vervet monkeys (Cercopithecus aethiops) progressively intoxicated with systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (0.3-0.4 mg/kg every 4-7 days). In the food preference task, the monkeys had to retrieve two types of directly visible food, simultaneously available in the wells of a reward board. At all stages of MPTP-induced parkinsonism, the monkeys continued to take their favourite food first. In the symbol discrimination task, the wells were covered with sliding plaques cued by symbols indicating the absence or presence of a reward, and the different types of food were blocked in separate sessions. Monkeys with mild or moderate parkinsonism made fewer attempts and took longer to retrieve non-preferred compared with preferred rewards. These results indicate that motivational processes are still able to direct (food preference task) and to urge (symbol discrimination task) behaviour in MPTP-lesioned monkeys. Such a functional preservation may be related to the relatively spared dopaminergic innervation of the limbic circuits that we found in our monkeys, in agreement with the literature on humans. Furthermore, the frequency of executive disorders (such as hesitations and freezing) appeared to be much lower with the preferred rewards. Thus, the preserved motivational processes may help to overcome executive dysfunction in the early stages of human PD.     

Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism. I. Effects of task complexity

Parkinson's disease (PD) is characterized by motor symptoms, usually accompanied by cognitive deficits. The question addressed in this study is whether complexity of routine actions can exacerbate parkinsonian disorders that are often considered to be motor symptoms. To examine this question, we trained four vervet monkeys (Cercopithecus aethiops) to perform three multiple-choice retrieval tasks. In order of ascending complexity, rewards were freely available (task 1), covered with transparent sliding plaques (task 2), and covered with opaque sliding plaques cued by symbols (task 3). Thus, from task 1 to task 2 we added a motor difficulty--the recall of context-adapted movement; and from task 2 to task 3 we added a cognitive difficulty: the recall of symbol-reward associations. The more complex the task, the longer it took to learn, but after extensive training the performance was stable in all tasks, with similar retrieval durations. The monkeys then received systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (0.3-0.4 mg/kg) every 4-7 days, until the first motor symptoms appeared. In the course of MPTP intoxication, the behavioural performance declined while the motor symptoms were absent or mild--the retrieval duration increased, and non-initiated choices and hesitations between choices became frequent. Interestingly, this decline was in proportion to task complexity, and was particularly pronounced with the cognitive difficulty. Furthermore, freezing appeared only with the cognitive difficulty. We therefore suggest that everyday cognitive difficulties may exacerbate hypokinesia (lack of initiation, abnormal slowness) and executive disorders (hesitations, freezing) in the early stages of human PD.     

Neuroprotective effects of subthalamic nucleus high-frequency stimulation on substantia nigra neurons in a Parkinson''s disease rat model

BACKGROUND: Deep-brain stimulation has proven to be beneficial in the treatment of Parkinson's disease (PD) patients. OBJECTIVE: To investigate the effects of high-frequency stimulation (HFS) to the subthalamic nucleus (STN) on neuronal apoptosis and apoptosis-related gene expression in the substantia nigra pars compacta, and to analyze the neuroprotective effect of HFS-STN. DESIGN, TIME AND SETTING: Neuronal morphology experiments were performed in the Beijing Nearosurgical Institute from May to December in 2005. MATERIALS: Forty healthy, adult, Sprague Dawley rats were used to establish a PD model with a unilateral microinjection of 6-hydroxydopamine into two target areas of the right medial forebrain bundle. 6-hydroxydopamine was purchased from Sigma (USA); high-frequency electrical stimulator was produced by World Precision Instruments (USA); Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) kit was a product of Nanjing Jiancheng Technology Co., Ltd. (China); and Bcl-2 and Bax protein assay kit were purchased from Wuhan Boster Bioengineering Co., Ltd. (China). METHODS: Forty rats were randomly divided into three groups. The stimulation group (n = 15) received HFS-STN on the day of PD modeling. The PD model group (n = 15) was used to establish the PD model. The control group (n = 1 0) was injected with normal saline containing 0.2 g/L ascorbic acid into two areas of the right medial forebrain bundle. MAIN OUTCOME MEASURES: Survival of dopaminergic neurons in the substantia nigra pars compacta was determined using Nissl staining. Apoptosis of dopaminergic neurons was detected using TUNEL techniques. Expression of anti-apoptotic protein, Bcl-2, and pro-apoptotic protein, Bax, were assayed by immunohistochemistry. RESULTS: Following 6-hydroxydopamine injection, the number of substantia nigra pars compacta neurons was reduced in the stimulation and PD model groups, compared to the control group. At 2 and 4 weeks post-surgery, the grey value of Nissl stained images was significantly less in the PD model and stimulation groups (P < 0.05), and the stimulation group exhibited greater grey values compared to the model group (P < 0.05). At 2 and 4 weeks post-surgery, the number of apoptotic neurons was significantly less in the stimulation group compared to the model group (P < 0.05). In addition, Bcl-2 and Bax expression, as well as the Bcl-2/Bax ratio, was much higher in the stimulation group compared to the model group (P < 0.05). CONCLUSION: HFS-STN has a neuroprotective effect on dopaminergic neurons in the substantia nigra pars eompacta of PD rats by promoting Bcl-2 expression, inhibiting Bax expression, and reducing the number of apoptotic dopaminergic neurons.     

Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline

Summary. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (−)-methamphetamine and (−)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors. Received February 1, 2001; accepted May 30, 2001     

Responses of pallidal neurons to striatal stimulation in monkeys with MPTP-induced parkinsonism

Extracellular single unit activity was recorded from neurons of the internal (GPi) and external (GPe) pallidal segments, and from 'border cells' (Bor) which are part of the nucleus basalis, in 2 cynomolgus monkeys rendered parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Cell counts showed that at least 90% of the nigral neurons of the compacta-type were degenerated. Electrical stimulation was applied to 3 sites bilaterally in the striatum: one in the caudate nucleus and 2 in the putamen. The results were compared to those obtained in intact monkeys. In the parkinsonians, more neurons of the 3 types responded to ipsilateral stimulation. The difference was even greater for contralateral responses, except in the case of Bor neurons. Greater proportions of the 3 types of neurons also responded to 2 and 3 sites and showed convergent responses to both the caudate nucleus and the putamen. The magnitude of the responses was larger. These results are in accordance with the excessive and unselective responses of the same neurons to passive limb movement, obtained in the same animals and described previously. The electrical stimulation allowed more detailed analyses of the responses. The major change in the responses of GPi and Bor neurons was the more frequent and larger late inhibitions, whereas the excitations were larger in GPe neurons. Long lasting oscillatory responses occurred frequently in the parkinsonians, mainly in GPi, and at frequencies close to the tremor displayed by the animals. Responses beginning with early inhibition were displayed by neurons located in the center of the pallidal zone of influence of each striatal stimulation site, as in intact animals, but in the GPi of the parkinsonians they were less frequently curtailed by excitation. Moreover, in the parkinsonians, the zones of influence were larger in both GPi and GPe, mainly because of the expansion of their periphery, where responses began with excitation and had lower thresholds than in intact animals. The dopamine agonist apomorphine normalized the responses in the parkinsonians. Thus, both the temporal and spatial magnitudes of inhibitions and excitations are abnormal at the output of the basal ganglia in parkinsonism.