A novel MPTP primate model of Parkinson's disease: neurochemical and clinical changes

Positron emission tomography (PET) and the dopamine (DA) metabolism tracer, 6-fluoro- -m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and the clinical stage of parkinsonism monkeys following either unilateral ICA MPTP infusion or unilateral ICA MPTP infusion and subsequent varying sequential systemic doses of MPTP. Clinical stage corresponded to PET measures of striatal DA metabolism, showing the usefulness of the overlesioned hemiparkinsonian monkey as a stable model of various stages of Parkinson's disease (PD).     

6-[F]Fluoro-

Single photon emission computed tomography (SPECT) and the dopamine (DA) transporter tracer, 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), were used to determine DA transporter density in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-lesioned monkeys with varying degrees of parkinsonism. The clinical stage of parkinsonism corresponded to SPECT measures of striatal DA transporter density suggesting that more severe parkinsonism was associated with a greater degree of dopaminergic terminal degeneration. These findings are similar to those reported earlier using positron emission tomography (PET) and the DA metabolism tracer, 6-[18F]fluoro-L-m-tyrosine (FMT), indicating that both are good methods for evaluating nigrostriatal degeneration in MPTP primate models.     

Dopamine transporter loss and clinical changes in MPTP-lesioned primates

Single photon emission computed tomography (SPECT) and the dopamine (DA) transporter tracer, 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT), were used to determine DA transporter density in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-lesioned monkeys with varying degrees of parkinsonism. The clinical stage of parkinsonism corresponded to SPECT measures of striatal DA transporter density suggesting that more severe parkinsonism was associated with a greater degree of dopaminergic terminal degeneration. These findings are similar to those reported earlier using positron emission tomography (PET) and the DA metabolism tracer, 6-[18F]fluoro-L-m-tyrosine (FMT), indicating that both are good methods for evaluating nigrostriatal degeneration in MPTP primate models.     

Local cerebral glucose utilization in monkeys with hemiparkinsonism induced by intracarotid infusion of the neurotoxin MPTP

Quantitative 2-[14C]deoxyglucose autoradiography was used to map the pattern of alterations in local cerebral glucose utilization associated with unilateral lesions of the substantia nigra pars compacta produced by the infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into one internal carotid artery of rhesus monkeys. These monkeys become hemiparkinsonian, displaying rigidity, bradykinesia, and tremor of the limbs contralateral to the side of MPTP infusion; during spontaneous activity they turn toward the side of the lesion. Eighty-two brain areas were examined, and statistically significant metabolic changes were confined mainly to basal ganglia structures ipsilateral to the side of the lesion. Glucose utilization was reduced in the substantia nigra pars compacta and ventral tegmental area, i.e., in the areas of cell loss. Increases in glucose utilization in regions normally innervated by the lesioned area were observed in the post-commissural portions of the putamen and dorsolateral caudate. Other structures showing statistically significant metabolic changes were the external segment of the globus pallidus (+40%), subthalamic nucleus (-17%), and pedunculopontine nucleus (+15%). There were also smaller changes in portions of the thalamus (ventral anterior nucleus, parafascicular nucleus) and premotor cortex. All significant metabolic changes were confined to the side of the substantia nigra lesion and were essentially restricted to regions involved in the production of movement or maintenance of posture.     

In vivo changes of catecholamines in hemiparkinsonian monkeys measured by microdialysis.

In monkeys, unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a useful model of hemiparkinsonism. To evaluate MPTP-induced neurochemical changes in vivo, brain microdialysis was employed to measure extracellular levels of dopamine and its metabolites in the neostriatum of normal and hemiparkinsonian rhesus monkeys (Macaca mulatta). The microdialysis probes were implanted bilaterally into the caudate nucleus and putamen at coordinates determined from magnetic resonance imaging. Dopamine and its metabolites were depleted in the MPTP-lesioned side versus the unlesioned side in hemiparkinsonian monkeys. Tyrosine hydroxylase immunocytochemistry revealed a complete unilateral denervation in the caudate nucleus and putamen and a total loss of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta in those monkeys. Baseline levels of amines in the neostriatum in normal monkeys were not significantly different from those in the normal (non-MPTP-treated) side in hemiparkinsonian monkeys. These data demonstrate that brain microdialysis is a valuable tool for measuring in vivo neurochemical changes in nonhuman primate brains.     

Neurochemical changes in the substantiae nigrae and caudate nuclei following acute unilateral intranigral infusions of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Acute unilateral intranigral infusions of MPTP at doses (200 micrograms) which produce robust contralateral rotation in the rat induced significant neurochemical changes in the ipsilateral as well as contralateral nigrostriatal systems. There were pronounced increases in the levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the ipsilateral substantia nigra and a significant decrease in the levels of DA in the ipsilateral caudate nucleus while opposite changes occurred in the contralateral substantia nigra and caudate nucleus. The DOPAC:DA and HVA:DA ratios were significantly higher in the ipsilateral caudate nucleus indicating increased activity of the ipsilateral nigrostriatal DA neurones. The levels of noradrenaline and 4-hydroxy-3-methoxyphenylethyline glycol (MHPG) increased and decreased significantly in the ipsilateral and contralateral substantia nigra, respectively, but there were no significant changes in the caudate nuclei. The levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased significantly in the ipsilateral substantia nigra and caudate nucleus as well as in the contralateral caudate nucleus but did not increase significantly in the contralateral substantia nigra. The 5-HIAA:5-HT ratio was significantly decreased in the contralateral caudate nucleus indicating a reduced activity of the contralateral nigrostriatal 5-HT neurones. The data thus indicate that MPTP applied to one substantia nigra is capable of producing profound neurochemical changes not only locally but also in the ipsilateral striatum as well as in the contralateral nigrostriatal system. Previous neuropharmacological studies have suggested that the rotation induced by intranigral MPTP may be mediated via dopamine released from dendrites in the pars reticulata in response to MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic exposure to low doses of MPTP. II. Neurochemical and pathological consequences in cognitively-impaired, motor asymptomatic monkeys

Chronic low-dose MPTP exposure was previously found to impair cognitive performance in monkeys. These monkeys developed deficits in performance of delayed response and delayed alternation tasks but maintained performance on visual pattern discrimination. This, along with other subtle behavioral changes, occurred in the absence of gross parkinsonian motor symptoms. The present study reports the results of neurochemical and neuropathological examination of the brains of these animals. Chronic low-dose MPTP exposure resulted in profound decreases in caudate dopamine (DA) levels and slightly less severe depletions in the putamen. Increases in striatal HVA/DA ratios suggest an increase in DA turnover in these areas. In contrast to striatal DA depletions, we found significant increases in striatal serotonin levels without an associated increase in serotonin turnover. At the cortical level, we found inconsistent changes in frontal cortical DA levels and variable decreases in norepinephrine levels. Since the most profound and consistent deficits were in the nigrostriatal dopamine system, we suggest that most of the behavioral consequences of chronic low-dose MPTP exposure stem from the striatal dopamine depletion. We also suggest that the maintenance of motor function in the presence of massive striatal DA depletions may be due to less impairment of putamen DA vs. caudate DA, by an increase in striatal DA turnover, a compensatory increase in serotonin availability, or a combination of these and possibly other as yet undetermined compensatory mechanisms. Furthermore, we propose the present model utilizing chronic low-dose exposure to MPTP as a model for the early, compensated form of Parkinson's disease.     

Relative sparing of the dopaminergic innervation of the globus pallidus in monkeys made hemi-parkinsonian by intracarotid MPTP infusion.

Tyrosine hydroxylase immunohistochemical analysis was performed on tissue sections through the pallidal complex from Nemistrina monkeys which had been made hemi-parkinsonian by intracarotid MPTP infusion 8-12 months earlier. The side contralateral to the MPTP infusion showed a dense dopaminergic innervation of the pallidum (both internal and external segments), but particularly the internal pallidum. The side of the brain ipsilateral to the MPTP infusion showed a remarkable sparing of the pallidal dopaminergic innervation, despite almost total loss of the dopaminergic innervation of the caudate and putamen. These results support the view that in the primate, the nigropallidal projection is mostly distinct from the nigrostriatal projection. It is also suggested that perhaps the sparing of pallidal dopamine at least in part may contribute to some of the recovery of function observed in some monkeys following exposure to MPTP.     

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on catecholamines and metabolites in primate brain and CSF

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration is able to produce nigrostriatal damage and motor disabilities in primates similar to those seen in Parkinson's disease. Two months after MPTP treatment in African Green monkeys, significant depletions of dopamine (DA) and/or homovanillic acid (HVA) were found in the dorsal ventral tegmental area, and septum, but not in the ventral part of the ventral tegmental area or nucleus accumbens. However, DA losses were greater at all examined sites in the striatum. In putamen and caudate nucleus the decreases in DA and HVA appeared more marked dorsolaterally than ventromedially. After MPTP treatment the ratio HVA/DA was elevated in the septum and all striatal regions; in the striatum the increases in ratio were greater in the dorsolateral than in the ventromedial samples. NE concentration was not significantly altered by MPTP in the mesolimbic system. In control animals the HVA concentration and the ratio HVA/DA were higher in the putamen than in the caudate nucleus. A longitudinal study showed that CSF HVA and 3-methoxy-4-hydroxyphenylglycol were reduced by MPTP and remained below baseline level for 12 months after MPTP treatment. This biochemical study indicates that in the monkey MPTP is able to induce selective damage within both the nigrostriatal and mesolimbic DA systems.     

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis)

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from monkeys which had received unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing loss of dopamine-containing neurones of the substantia nigra pars compacta. The monkeys developed hemi-parkinsonian symptoms (tremor, bradykinesia) in limbs contralateral to the side of the toxin infusion. Administration of apomorphine (0.05-0.25 mg/kg) caused contralateral rotational behaviour, and reversal of the parkinsonian symptoms. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A reduction in these sites of 97% (mean brain value) in the caudate nucleus, and 91% in the putamen, as compared with binding values from untreated control monkeys, was accompanied by a significant increase in the binding of [3H]sulpiride (D2) in these structures. In contrast, in the same animals there was no similar increase in [3H]SCH 23390 binding to D1 receptors in the denervated areas. These results suggest that in the parkinsonian brain, where the dopaminergic innervation of the caudate nucleus and putamen has been lost, D2 receptors may be more susceptible than D1 receptors to changes, revealed here as an increase in [3H]sulpiride binding sites.     

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.     

Spontaneous saccades in MPTP-induced hemi-parkinsonian monkeys

The basal ganglia play an important role in the control of saccadic eye movements. Parkinsonian patients have deficits in saccade initiation; the deficits are more prominent in memory-guided saccade than in visually guided saccade (Hikosaka et al, 1987). These results show that deficiency of nigrostriatal dopaminergic system affects the neural mechanism of saccadic eye movements in the basal ganglia. In order to investigate this hypothesis, we studied saccadic eye movements in MPTP-induced hemiparkinsonian monkeys. We made two models of parkinsonism using two monkeys: 1) unilateral intra-carotid injection of MPTP, and 2) intracaudate injection of MPTP using osmotic minipump. We recorded saccadic eye movements using the magnetic search coil method. After experiments, monkeys were sacrificed and investigated by histological procedures. Following the intracarotid injection, we observed hypokinesia and rigidity in the arm and leg contralateral to the injection. Eye position was shifted to the ipsilateral side and the frequency of saccades towards the contralateral side was reduced. Following the intracaudate injection, we observed hypokinesia and rigidity in the contralateral arm and leg and circling behavior towards the contralateral side. In both monkeys, the saccade amplitude and peak velocity towards contralateral side were reduced. We considered three mechanisms that might account for these results. First, dopaminergic denervation due to MPTP in the caudate nucleus may suppress the activity of neurons projecting to the pars reticulata of the substantia nigra. Second, nigra cell activity may be tonically elevated through an indirect pathway via the external pallidum and the subthalamic nucleus. Third, MPTP may enhance nigra cell activity through dendro-dendritic connections from the pars compacta to the pars reticulata in the substantia nigra.     

Prevention of dyskinesia by an NMDA receptor antagonist in MPTP monkeys: effect on adenosine A2A receptors

Adenosine A(2A) receptors (A(2A)R) have received increasing attention for the treatment of L-DOPA-induced dyskinesias in Parkinson disease. In the present study, A(2A)R messenger RNA (mRNA) and receptor-specific binding in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys were studied after treatment with L-DOPA and a selective NR1A/2B NMDA receptor antagonist, CI-1041. Four MPTP monkeys received L-DOPA/benserazide and all developed dyskinesias, whereas among the four MPTP monkeys who additionally received CI-1041, only one developed mild dyskinesias. Four normal monkeys and four MPTP-treated monkeys were also studied. All MPTP monkeys had similar striatal dopamine (DA) denervation. A(2A)R mRNA levels, measured by in situ hybridization, were increased in the rostral lateral caudate and putamen of saline-treated MPTP monkeys as well as in the caudal lateral and medial putamen when compared with those of controls. A(2A)R mRNA levels remained elevated in the rostral caudate and putamen of L-DOPA-treated MPTP monkeys when compared with those of controls. A(2A)R mRNA levels of L-DOPA + CI-1041-treated monkeys were at control levels and decreased in the lateral rostral caudate and caudal putamen when compared with those of L-DOPA-treated and saline-treated MPTP monkeys respectively. No change was measured in the caudal medial putamen and caudate nucleus. A(2A)Rs labeled by autoradiography with [(3)H]SCH-58261 had lower level in the L-DOPA + CI-1041-treated MPTP monkeys compared with saline- or L-DOPA-treated MPTP and control monkeys in the rostral lateral and medial caudate and the putamen. No effect of lesion or L-DOPA treatment was measured on [(3)H]SCH-58261-specific binding. These findings suggest that blockade of NMDA receptors could prevent the development of dyskinesias by altering A(2A)Rs.     

Dopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated hemiparkinsonian monkeys]

Infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right common carotid artery of 5 rhesus monkeys produced hemiparkinsonian syndrome in the contralateral limbs which responded to madopa or apomorphine therapy. Moreover, these two drugs induced circling away from the MPTP-treated side, amphetamine induced rotation toward the MPTP-treated side. Long-term use of madopa developed a peak-dose dyskinesia of the face and the limbs contralateral to the MPTP-treated side. The ipsilateral toxic effects were confirmed biochemically by reduction of nigrostriatal DA and histologically by degeneration of nigral neurons of the MPTP-treated side. It is concluded that this hemiparkinsonian model of rhesus monkey will be of value in the elucidation of the neural mechanism underlying L-DOPA or DA agonist induced dyskinesia in Parkinson's disease and in the search for newer methods of treatment which would produce less dyskinesia and response fluctuations.     

Dopaminergic denervation and spine loss in the striatum of MPTP-treated monkeys

Striatal spine loss is a key pathological feature of human Parkinson's disease (PD) that can be induced after complete degeneration of the nigrostriatal dopaminergic system in rodent models of parkinsonism. In line with these observations, our findings reveal a significant (30–50%) reduction in spine density in both the caudate nucleus and putamen of severely DA-depleted striata of MPTP-treated monkeys; the sensorimotor post-commissural putamen being the most severely affected region for both dopamine depletion and spine loss. Using MPTP-treated monkeys with complete or partial striatal dopamine (DA) denervation, we also demonstrate that striatal spine loss is an early pathological feature of parkinsonism, which progresses along a positive rostrocaudal and mediolateral gradient in parallel with the extent of striatal dopamine denervation. Quantitative electron microscopy immunocytochemistry for D1 dopamine receptor (D1) in the striatum of control and severely DA-depleted animals revealed that both D1-immunoreactive and immunonegative spines are lost in the putamen of MPTP-treated monkeys.These data demonstrate that striatal spine loss in MPTP-treated monkeys is an early pathological event of parkinsonism, tightly correlated with the degree of nigrostriatal dopamine denervation that likely affects both direct and indirect striatofugal pathways.     

Correlation of Parkinson's disease severity and duration with 123I-FP-CIT SPECT striatal uptake.

The variability in clinical features and the masking effects of drug therapy in Parkinson's disease (PD) can affect clinical assessment of disease severity. The aim of this study was to assess the imaging of dopamine transporters using 123I-FP-CIT SPECT and its correlation with disease staging, severity, and duration. Differences between the clinical severity of the onset and non-onset side and the corresponding striatal uptake ratios were also examined. Forty-one patients with PD (nine unilateral, 32 bilateral clinical features) were studied. Clinical severity was determined by using the Unified Parkinson's Disease Rating Score (UPDRS). Unilateral UPDRS was calculated from unilateral arm and leg resting and action tremor, rigidity, finger taps, hand movements, alternating movements, and leg agility. 123I-FP-CIT striatal uptake was expressed as the ratio of specific:nonspecific (SP:NS) uptake for defined brain areas. Patients with PD who had unilateral symptoms showed a significant difference between the ipsilateral and contralateral SP:NS ratios in both the caudate and putamen, but there was a considerable overlap between between the two sides. This result was repeated in patients with bilateral symptoms and there was overlap of SP:NS ratios between the two groups. For the whole group of patients with PD, striatum, caudate, and putamen SP:NS ratios correlated with disease severity assessed by UPDRS and duration of disease. The SP:NS ratios correlated with the bradykinesia subscore but not with rigidity or tremor subscore. In conclusion, this study provides further evidence that the SP:NS ratio is a robust measure of disease severity correlating with duration of PD. However, variability in uptake values suggest that factors other than nigrostriatal degeneration may contribute to disease severity. Correlation with bradykinesia but not with tremor may indicate an origin for tremor outwith the dopamine transporter system. 123I-FP-CIT SPECT offers significant potential in defining the nigrostriatal changes in PD.     

在体检测偏侧帕金森病猴模型尾核区多巴胺含量

本实验应用1-甲基-1,2,3,6-四氢吡啶(MPTP)制备偏侧帕金森病(PD)猴模型,采用颅内微透析技术结合高效液相色谱-电化学法(HPLC-EC)在体检测双侧尾核区多巴胺(DA)及其代谢产物的含量。结果发现,注射侧与注射对侧相比,尾核区DA、二羟苯乙酸(DOPAC)及高香草酸(HVA)的含量分别减少70％、34％和38％。结果表明:颅内微透析技术是在体检测脑内神经递质含量的最有效方法,可以直接反映与PD样症状有关的细胞外液神经递质的变化。     

Diagnostic utility of positron emission tomography for parkinsonism after chronic manganese exposure]

Positron emission tomography (PET) with [18F] 6-fluoro-L-dopa (18F-FDOPA) was performed in three South Korean patients with parkinsonism who developed after chronic manganese exposure. A 51-year-old man (patient 1) suffered from masked face, marked postural tremor of hands, dystonia in the neck and the upper extremities, severe retropulsion and lateropulsion which were typical for chronic manganese intoxication. 18F-FDOPA scan was normal. Other two patients, a 46-year-old man (patient 2) and a 47-year-old man (patient 3), showed tremor at rest and rigidity predominantly on the right side, bradykinesia, stooped posture and postural instability; all of these were typical for Parkinson's disease (PD). There was reduced uptake of 18F-FDOPA in the striatum, particularly in the posterior putamen predominant on the left side, in both patient 2 and 3. From these results, patient 1 was diagnosed as pure manganism, while patient 2 and 3 were primarily as PD, because loss of nigrostriatal fibers was obvious with asymmetry of affection in the putamen. PET with 18F-FDOPA provides valuable information for differentiation between PD and manganism, although it is not clear whether development of parkinsonian symptoms in patient 2 and 3 was modified by excessive manganese exposure.     

Levodopa responsive parkinsonism in an adult with Huntington's disease

A patient is reported on with Huntington's disease who, as anadult, first developed severe parkinsonism with bradykinesia, rigidity,postural instability and festinating gait. His clinical signs weresimilar to those of the Westphal variant of Huntington's diseaseexcept that he also had resting tremor and a supranuclear gaze palsy.Magnetic resonance imaging showed caudate and putamen atrophy. Geneticanalysis disclosed 49 triple CAG repeats in allele 1 and 17 in allele 2 confirming the diagnosis of Huntington's disease. Treatment withlevodopa produced substantial functional motor improvement with a 17 point reduction in the unified Parkinson's disease rating scale(UPDRS) motor subscale including reduction of tremor, bradykinesia, andpostural instability. This is the first report of a patient with adultonset Huntington's disease with parkinsonism responsive to levodopa.

     

Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The right common carotid artery was surgically exposed under general anaesthesia in 6 cynomolgus monkeys and MPTP (0.5–2.2 mg/kg) directly infused. This produced a hemiparkinsonian syndrome in the contralateral limbs which responded to treatment with both levodopa and apomorphine. these drugs also precipitated dose-dependent contralateral rotation which reached a peak 2 weeks after MPTP infusion. A massive depletion of large, presumably dopaminergic cells was found from the ipsilateral substantia nigra pars compacta. Three animals receiving chronic therapy with apomorphine developed choreoathetoid movements of the limbs and the face contralateral to the infusion 2 weeks after the commencement of treatment. The severity of the dyskinesia gradually increased and after 4 weeks peak-dose hemiballistic movements were seen. Levodopa and the selective D-2 and D-1 dopamine agonists LY-171555 and SKF 38393 also reversed parkinsonian features and produced contralateral rotation and peak-dose dyskinesia. This unilateral model of parkinsonism in the primate will be of value in the elucidation of the mechanisms by which chronic levodopa or dopamine agonist therapy enhance involuntary movements in parkinsonism.