Involvement of monoamine oxidase enzymes in the action of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, a selective neurotoxin, in the squirrel monkey: Binding and biochemical studies

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a new neurotoxin that causes degeneration of the dopaminergic nigrostriatal neurons and induces a Parkinson-like state in several species, including humans and monkeys. The present study was designed to better characterize the properties of [3H]MPTP binding sites and to evaluate the interaction of MPTP with the oxidation of dopamine by monoamine oxidase (MAO) in an animal species (Saimiri Sciureus) shown to be lesioned by MPTP. Our data confirm the presence of high affinity and saturable binding sites for [3H]MPTP in the squirrel monkey. Specific binding with analogous characteristics also occurs in peripheral tissues. Various substances failed to inhibit the [3H]MPTP binding, whereas only MAO inhibitors (MAOI) were able to antagonize this binding to brain and peripheral tissues. In particular, deprenyl, a selective inhibitor of MAO type B enzyme, was relatively more potent as a displacer of [3H]MPTP from its binding sites both in brain and in peripheral tissues. Our results further suggest a correspondence between [3H]MPTP sites and MAO, particularly MAO-B, in monkey brain. Moreover, our data show that the oxidative deamination of dopamine is inhibited by MPTP in vitro. In conclusion, these data are consistent with the hypothesis of the involvement of MAO in the neurotoxic effects of MPTP, even though further experiments are necessary to better clarify the molecular mechanism of MPTP neurotoxicity.     

皮下注射MPTP诱导猕猴双侧慢性帕金森病模型的制作

目的探讨猕猴双侧慢性不可逆性帕金森病（PD）模型的制作方法。方法 4只猕猴分别采用不同剂量（0.1 mg/kg/d和0.4 mg/kg/d）和不同频率（每天一次和隔天一次）及不同次数皮下注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）制作PD模型,注射MPTP前后观察行为学表现并进行非人类灵长类PD评分量表（PPRS）评分。结果猕猴注射MPTP一段时间后开始出现PD症状,主要表现为倦怠、迟缓;继续给药PD症状会出现进行性快速加重导致后续动物因进食困难而死亡;若过早停止给药,则导致PD模型不稳定,动物症状可自愈。采用剂量为0.1 mg/kg/d的MPTP连续皮下注射14 d后,猕猴出现中度PD症状（PPRS评分为6~8分）时,改隔日注射一次,共4次,猕猴出现不可逆性PD症状,且可自主摄食并长期存活,是一个成功的模型。结论适量皮下注射MPTP可制作猕猴慢性、不可逆性、双侧PD模型,其更接近人PD的临床特征,且无需鼻饲喂养可长期存活。     

Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys

Systemic administration of the recently discovered neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces severe clinical parkinsonism and degeneration of the substantia nigra in humans and monkeys. In previous studies, no convincing structural damage to nerve cells outside the substantia nigra could be demonstrated in subhuman primates. Using a protracted MPTP regimen and older animals, we now report locus ceruleus lesions and eosinophilic inclusion bodies in squirrel monkeys. The inclusions were seen only in areas where Lewy bodies are found in human Parkinson's disease. No such abnormalities were seen in control animals. These findings suggest that similarities between the neuropathology of MPTP-induced parkinsonism in the monkey and human Parkinson's disease are greater than first thought and increase the usefulness of the MPTP monkey model for research in Parkinson's disease.     

Study of an MPTP-induced parkinsonian animal model in the rhesus monkey and the mechanism of the action of MPTP

In this paper are presented the data of the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to create a parkinsonian animal model in rhesus monkey. We studied the mechanism of the action of MPTP through testing monoamine oxidase B (MAO-B) inhibitor, deprenyl and L-prolyl-L-leucyl-glycinamide (PLG) against the neurotoxicity of MPTP. The results indicated that: (1) the use of MPTP can establish a useful parkinsonian animal model in rhesus monkey; (2) pretreatment with deprenyl can effectively prevent the neurotoxicity of MPTP; and (3) whether PLG can prevent or alleviate the neurotoxicity of MPTP requires further study.     

Disappearance of circadian rhythms in Parkinson''s disease model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in dogs

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to dogs produces clinical, pathological and neurological features in dog resembling human Parkinson's disease. Using this animal model, we studied the changes in diurnal rhythms of urine volume, creatinine in urine, and vasopressin, aldosterone and renin activity in plasma. Before MPTP treatment, urine volume showed a peak between 17.00 and 1.00 and plasma vasopressin concentration also showed a clear circadian rhythm with a peak at 13.00 and a minimum level at 5.00. Two weeks after MPTP treatment (2.5 mg/kg i.v.), the rhythm of urine volume disappeared and that of vasopressin became less clear. Plasma renin activity increased 2 and 4 weeks after MPTP treatment. The increase was, however, not enough to change the concentration of plasma aldosterone. We examined the effect of L-3,4-dihydroxyphenylalanine (levodopa), on the circadian pattern of urine volume and vasopressin attenuated by MPTP. Levodopa (4 mg/kg/day) was administered orally every day from the first week after MPTP treatment. The circadian rhythms of urine volume and vasopressin reappeared within one week after the start of levodopa administration.     

Vigilance states in a parkinsonian model, the MPTP mouse

Sleep disturbances and vigilance disorders are frequently observed in Parkinson's disease. Despite the fact that the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse is one of the best-known animal models of Parkinson's disease, sleep analysis has never previously been performed in this system. In the present study, we explored sleep-wakefulness cycles in MPTP-treated mice and compared the results to data from untreated mice. MPTP (25 mg/kg) was injected daily for 5 days. After recovery, polysomnography was recorded over 48 h. Dopaminergic lesions of the substantia nigra and striata were evaluated using immunohistochemical markers. Immunohistochemical analysis showed a loss of dopaminergic neurons in MPTP mice. Compared with controls, MPTP-treated mice presented changes in sleep architecture throughout the nycthemeral period, with longer wakefulness and paradoxical sleep episodes and an increase in the amount of paradoxical sleep. We observed changes in sleep architecture in MPTP-treated mice, compared with saline-treated mice. MPTP mice show more consolidated vigilance states with higher amount of paradoxical sleep than controls. Although the MPTP-treated mouse is not a good model of sleep disturbances in PD, our results suggest that it could be a good pharmacological model for studying the effects of dopaminergic treatments on animal sleep-wakefulness cycles.     

The evolution of nigrostriatal neurochemical changes in the MPTP-treated squirrel monkey

The MPTP-treated monkey has become an important model for the study of Parkinson's disease. However, studies on the acute evolution of the neurotoxic effects of MPTP in primates are lacking. In the present study, 17 squirrel monkeys were given a single subcutaneous injection of MPTP (2.5 mg/kg). The behavioral effects and the concentrations of dopamine (DA), dihydroxyphenylacetic acid and homovanillic acid were determined in caudate, putamen and substantia nigra 1, 3, 5 (n = 3/time point) and 10 days (n = 6) after drug administration. Two animals were studied neuropathologically 8 and 9 days after MPTP. Profound parkinsonism was evident in all animals after 1 day and neuropathological examination revealed severe nerve cell destruction in the substantia nigra. Surprisingly, although 50-75% reductions in nigral DA were observed 1 and 3 days after MPTP, caudate DA was not reduced and putaminal DA was increased at these time points. The temporal sequence of these events differs markedly from that which occurs in the MPTP-treated mouse and suggests that, in the monkey, nigral cell bodies may represent an important initial site of MPTP-induced damage. Five and 10 days after MPTP, nigral DA depletions remained greater than 60% of control and striatal DA was reduced 50-85%. At these time points, the putamen was always more affected than the caudate. This interregional pattern of striatal DA deficits is similar to that seen in idiopathic Parkinson's disease.     

A mouse model of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinsonism: effect of norepinephrine terminal destruction

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been reported to cause chronic Parkinsonism in humans, primates, and long lasting striatal dopamine depletion in mice. Acute animal models thus produced closely resemble Parkinson's disease. There are, however, two major differences. The one is a lack of Lewy bodies and the other is that norepinephrine system is relatively well preserved in the model. So the acute animal model is better considered a nigrostriatal dopamine deficiency model. We have produced another model by adding N-2-chloroethyl-N-ethyl-2-bromobenzyl-amine (DSP4) to MPTP. This material is known to produce selective destruction of norepinephrine terminal in the central nervous system as well as in the periphery. Both norepinephrine system and dopamine system are severely depressed in this model, and the functional role of norepinephrine system was investigated by comparing two models. 90 male C57 black mice weighing 20-25 grams were used. MPTP (Aldrich) was dissolved in sterile distilled water with 5% ethanol solution. Experimental animals were divided into three groups. i) control group; in this group animals received vehicles alone. ii) MPTP group; in this group, mice received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days, thus total doses of MPTP was 300 mg/kg. iii) MPTP & DSP4 group; in this group animals received daily i.p. doses of MPTP 30 mg/kg for consecutive 10 days and at the last day of MPTP injection they received DSP4 50 mg/kg i.p.. 7 to 14 days after the last injection of MPTP both treated and control mice received an intraperitoneal injection of L-DOPA (200 mg/kg & aromatic L-amino acid decarboxylase mg/kg) and the effect of this drug on three groups were investigated by using behavioral, biochemical and histofluorescence method. Histofluorescence studies by GA-FAS method revealed severe reduction of nigrostriatal dopamine in MPTP treated mice. Mesolimbic and mesocortical dopamine systems seemed relatively preserved. There was no apparent changes in locus coeruleus norepinephrine system. In MPTP & DSP4 treated mice marked reduction of norepinephrine terminal fluorescence as well as nigrostriatal dopamine system was observed. Chemical analysis of norepinephrine and dopamine by HPLC confirmed histofluorescence studies. Behavioral studies were analyzed by Automex locomotor activity meter. Marked increase of locomotor activity was observed in MPTP treated mice after L-DOPA administration.(ABSTRACT TRUNCATED AT 400 WORDS)     

MPTP is proconvulsant acutely but has no long-term effect in rodent models of seizure and epilepsy

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was used to lesion the substantia nigra of rodents to look for changes in various animal models of epilepsy and seizures. MPTP, acutely administered to C57BL/6J mice, could cause seizures at high doses and enhanced maximal electroshock seizures at lower doses. Older mice were more sensitive to MPTP toxicity. MPTP given over 1 week to produce a 75% drop of striatal dopamine had no effect on seizure thresholds to pentylenetetrazol or picrotoxin and did not change the maximal electroshock seizure. Epileptic gerbils given maximally tolerated doses of MPTP had only a slight striatal dopamine reduction (32%) while seizures remained unaltered. The data are consistent with the hypothesis that chronic dysfunction of dopamine containing substantia nigra neurons have no significant influence on seizures in these animal models.     

Symptoms and behavioral features induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an old Java monkey [Macaca cynomolgus fascicularis (Raffles)]

The study concerns symptoms and behavioral characteristics induced by MPTP in a 20-year-old Macaca cynomolgus fascicularis, their evolution over 7 months, and the animal's response to 1-dopa treatment. The symptoms which the animal developed include those that have been described earlier in Macaca mulatta and Saimiri sciureus, i.e., rigidity, action tremor, postural tremor, postural flexion, hypokinesia, and bradykinesia. In addition, however, the animal developed a 3.8 Hz resting tremor which in humans is pathognomonic of Parkinson's disease, as well as cogwheeling, the glabellar tap sign, drooling, impaired ability to relax, and many other symptoms. Also unlike previously described MPTP monkeys, the animal's symptoms neither improved spontaneously, nor did they remain stable shortly after MPTP injection. Instead, symptoms steadily progressed to reach a severe status 2 months after MPTP, and further progression was apparent after another 5 months. Therapeutic responses to 1-dopa required accumulation of or kindling by the 100 mg unit doses that were spaced 4 hr apart, were often organized in time as ON episodes that alternated with OFF episodes, and were associated with dyskinesias and bizarre behavior. Of particular interest is that the animal showed kinesia paradoxa which, in humans, constitutes a feature that is unique to Parkinson's disease among the extrapyramidal disorders. In addition to available evidence, the present findings validate the syndrome induced by MPTP in monkey as an animal analogue of Parkinson's disease. Taxonomic category, age, and the occurrence of shock in response to MPTP are discussed as variables that may possibly co-determine the pathology which MPTP may induce in monkey.     

The hyperkinetic abnormal movements scale: a tool for measuring levodopa-induced abnormal movements in squirrel monkeys.

The Hyperkinetic Abnormal Movements Scale (HAMS) was developed based on extensive observation of normal and abnormal movements in squirrel monkeys. The observations of abnormal movements were performed using animals that had undergone prior lesioning with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that subsequently developed levodopa-induced abnormal movements. Specific and easily observable changes in behavior were used to delineate the boundaries between each rating level of the scale. The full spectrum of abnormal behavior at each rating level was then characterized for the squirrel monkey. Once the scale was fully developed and finalized, reliability testing revealed strong inter-rater (r = 0.959) and intrarater reliability (r = 0.930 to 0.941). Novice raters were easily taught its use and subsequently could use the scale with strong inter-rater reliability (R = 0.9057). In further studies of levodopa-induced abnormal movements, the HAMS was demonstrated to be highly sensitive, highly specific, and valid, both internally and when compared with an objective measure of abnormal movements. Although the scale was developed in MPTP-lesioned squirrel monkeys treated with levodopa, it might provide a framework for the standardized measurement of hyperkinetic abnormal movements in other primates and other experimental conditions.     

Fate of nigrostriatal neurons in young mature mice given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A neurochemical and morphological reassessment

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on nigrostriatal dopaminergic neurons in the mouse was re-examined in view of recent conflicting reports regarding the neurotoxic effect of MPTP in this experimental animal. It was found that while MPTP destroyed a substantial number of dopaminergic nerve terminals in the striatum of young mature (6-8 weeks old) mice, it left the majority of cells in the pars compacta of the substantia nigra (SNc) unaffected. It was also found that 5 months after MPTP treatment there was substantial, although incomplete, recovery of striatal DA nerve terminal markers (DA level, metabolites, uptake, [3H]mazindol binding). Given these observations, it is concluded that while the young mature MPTP mouse may not be a valid animal model of Parkinson's disease (since it does not develop severe SNc cell loss characteristic of this disorder), it will be valuable for the study of how MPTP destroys dopaminergic nerve terminals and may prove useful as an experimental system for studying recovery of dopaminergic fibers after injury and for exploring ways to accelerate this recovery.     

The mouse MPTP model: gene expression changes in dopaminergic neurons

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Although valuable animal models have been developed, our knowledge of the aetiology and pathogenic factors implicated in PD is still insufficient to develop causal therapeutic strategies aimed at halting its progression. The neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most valuable models for analysing pathological aspects of PD. In this paper we studied the gene expression patterns underlying the pathogenesis of MPTP-induced neurodegeneration. We treated young and old C57BL/6 mice with different schedules of MPTP to induce degenerative processes that vary in intensity and time-course. During the first week after intoxication we used nonradioactive in situ-hybridization to investigate the expression patterns of genes associated with (i) dopamine metabolism and signalling; (ii) familial forms of PD; (iii) protein folding and (iv) energy metabolism. MPTP injections induced different severities of neuronal injury depending on the age of the animals and the schedule of administration as well as a significant degeneration in the striatum. In situ hybridization showed that MPTP intoxication initiated a number of gene expression changes that (i) were restricted to the neurons of the substantia nigra pars compacta; (ii) were correlated in intensity and number of changes with the age of the animals and the severity of histopathological disturbances; (iii) displayed in each a significant down-regulation by the end of one week after the last MPTP injection, but (iv) varied within one MPTP regimen in expression levels during the observation period. The subacute injection of MPTP into one-year-old mice induced the most severe changes in gene expression. All genes investigated were affected. However, alpha-synuclein was the only gene that was exclusively up-regulated in MPTP-treated animals displaying cell death.     

Selective alterations of gene expression in mice induced by MPTP

1-methyl-4-phenyl-1,2,4,6,-tetrahydropyridine (MPTP) is a selective neurotoxin that produces striatal dopamine depletion resulting in parkinsonism like symptoms in humans and is, therefore, used to generate animal models for Parkinson's disease (PD). In this study, C57BL/6N mice were treated with MPTP acutely (3x20 mg/kg, 2-hour interval, one day injection). Mice were then sacrificed 24 hours after the last injection and brain tissue was collected for analysis. Significant decrease of striatal dopamine (DA) and the metabolites (DOPAC, HVA) was observed after MPTP treatment. MPTP also reduced protein expression of tyrosine hydroxylase (TH) in the striatum. Real time RT-PCR was used to examine selective genes of the dopaminergic system in the substantia nigra. Our data demonstrated that MPTP significantly decreased gene expression of TH, dopamine transporter (DAT), and vesicle monoamine transporter (VMAT), coinciding with the pattern of dopamine concentration changes and protein expression after MPTP treatment. Although a significant decrease of DA metabolites was observed in striatum, there was no change in the expression of monoamine oxidases (MAO-A, MAO-B) or catechol O-methyltransferase (COMT), indicating that these changes might be simply a consequence of reduced monoamine levels. In addition, gene expression of alpha-synuclein was also decreased with MPTP treatment, but there was no change in beta-synuclein and parkin. This is the first study using real-time PCR to indicate that MPTP selectively alters gene expression and provides information for clinical studies in PD. Future studies will focus on gene expression of other pathways that may be affected by MPTP treatment and investigation of gene expression in specific cell types in vivo using LCM technology.     

Symptoms and behavioral features induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an old java monkey [Macaca cynamolgus fascicularis (Raffles)]

The study concerns symptoms and behavioral characteristics induced by MPTP in a 20-year-old Macaca cynamolgus fascicularis, their evolution over 7 months, and the animal's response to l-dopa treatment. The symptoms which the animal developed include those that have been described earlier in Macaca mulatta and Saimirus sciureus, i.e., rigidity, action tremor, postural tremor, postural flexion, hypokinesia, and bradykinesia. In addition, however, the animal developed a 3.8 Hz resting tremor which in humans is pathognomonic of Parkinson's disease, as well as cogwheeling, the glabellar tap sign, drooling, impaired ability to relax, and many other symptoms. Also unlike previously described MPTP monkeys, the animal's symptoms neither improved spontaneously, nor did they remain stable shortly after MPTP injection. Instead, symptoms steadily progressed to reach a severe status 2 months after MPTP, and further progression was apparent after another 5 months. Therapeutic responses to l-dopa required accumulation of or kindling by the 100 mg unit doses that were spaced 4 hr apart, were often organized in time as ON episodes that alternated with OFF episodes, and were associated with dyskinesias and bizarre behavior. Of particular interest is that the animal showed kinesia paradoxa which, in humans, constitutes a feature that is unique to Parkinson's disease among the extrapyramidal disorders. In addition to available evidence, the present findings validate the syndrome induced by MPTP in monkey as an animal analogue of Parkinson's disease. Taxonomic category, age, and the occurrence of shock in response to MPTP are discussed as variables that may possibly co-determine the pathology which MPTP may induce in monkey.     

Lamination of the lateral geniculate nucleus in the squirrel monkey,Saimiri sciureus

The parvocellular portion of the lateral gesticulate nucleus (LGN) in the squirrel monkey (Saimiri sciureus) is a relatively unlaminated mass of cells. In order to determine whether a concealed laminar structure might exist, one eye was removed in each of three squirrel monkeys. Transneuronal degeneration did not appear prominent in the LGN of the animal which was allowed to survive for six months, but in the two animals which survived for one year six laminae were clearly present. There was transneuronal degeneration in layers 1, 4 and 6 contralateral to the enucleation, and 2, 3 and 5 ipsilaterally. Lack of interlaminar fiber masses probably accounts for the apparent absence of lamination in the normal parvocellular mass.     

Behavioral motor recovery in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned squirrel monkey (Saimiri sciureus): changes in striatal dopamine and expression of tyrosine hydroxylase and dopamine transporter proteins

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.     

甲基—苯基—四氢吡啶增加脑糖代谢与Deprenyl对其拮抗作用的实验研究

应用[~3H]2-脱氧葡萄糖(2-DG)放射自显影法观察单胺氧化酶B型(MAO-B)抑制剂Deprenyl和神经毒素甲基-苯基-四氢吡啶(MPTP)对小鼠脑2-DG摄取的影响。腹腔注射MPTP后,模型组鼠的黑质和蓝斑区的2-DG摄取量较对照组鼠明显增加,并表现出明显的行为异常反应。预先口服Deprenyl的拮抗组鼠,2-DG摄取量与对照组相同,且行为反应轻微。结果表明MPTP对小鼠黑质和蓝斑区的局部糖利用有明显影响;Deprenly能有效防止MPTP的这一有害作用。     

NMDA受体和GABA受体拮抗剂对小鼠脑内多巴胺的影响

目的 观察兴奋性氨基酸受体拮抗剂和GABA受体拮抗剂对帕金森病（PD）模型动物全脑多巴胺（DA）含量的影响，为PD发病机制研究提供理论依据。方法 采用MPTP腹腔注射建立C57 BL小鼠PD模型，同时分别腹腔注射兴奋性氨基酸NMDA受体拮抗剂ketamine和GABA受体拮抗剂bicucullin．采用荧光分光光度计法测定各组小鼠全脑DA的含量。结果 ketamine＋MPTP组、bicucullin＋MPTP组与MPTP组及NS组比较，DA含量差异有统计学意义。结论 NMDA受体拮抗剂可抑制由MPTP引起的DA神经递质减少，GABA受体拮抗剂可增强MPTP引起的DA神经递质减少。     

Assessment of motor behavior using a video system and a clinical rating scale in parkinsonian monkeys lesioned by MPTP

The best current model of Parkinson's disease is the primate treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Quantification of animal movement is important for the study of severity of parkinsonian syndrome induced by MPTP and response to drug treatments. Both require clinical rating scales that measure motor behavior with well-defined objective items. However, evaluations using these scales depend on the observer scoring the different items, according to his/her experience. The video image analyzer system, which produces an activity curve in correlation with the visual study of animal motor behavior, offers an automatic evaluation method that is observer-independent and reproducible. Using such an system we defined items correlated with those used in clinical rating scales that are sensitive to animal motor changes, decrease in movements with MPTP intoxication and alleviation afforded by levodopa: global locomotor activity and specific activities (climbing, social interactions, eating and drinking behaviors).