MPTP-lesioned Macaques Research Articles

Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson’s disease primate model

Metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to the neurotoxin MPP+ in the brain causes permanent Parkinson’s disease-like symptoms by destroying dopaminergic neurons in the pars compacta of the substantia nigra in humans and non-human primates. However, the complete molecular pathology underlying MPTP-induced parkinsonism remains poorly understood. We used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging to thoroughly image numerous glycerophospholipids and sphingolipids in coronal brain tissue sections of MPTP-lesioned and control non-human primate brains (Macaca mulatta). The results revealed specific distributions of several sulfatide lipid molecules based on chain-length, number of double bonds, and importantly, hydroxylation stage. More specifically, certain long-chain hydroxylated sulfatides with polyunsaturated chains in the molecular structure were depleted within motor-related brain regions in the MPTP-lesioned animals, e.g., external and internal segments of globus pallidus and substantia nigra pars reticulata. In contrast, certain long-chain non-hydroxylated sulfatides were found to be elevated within the same brain regions. These findings demonstrate region-specific dysregulation of sulfatide metabolism within the MPTP-lesioned macaque brain. The depletion of long-chain hydroxylated sulfatides in the MPTP-induced pathology indicates oxidative stress and oligodendrocyte/myelin damage within the pathologically relevant brain regions. Hence, the presented findings improve our current understanding of the molecular pathology of MPTP-induced parkinsonism within primate brains, and provide a basis for further research regarding the role of dysregulated sulfatide metabolism in PD.

The levels of the NMDA receptor co-agonist D-serine are reduced in the substantia nigra of MPTP-lesioned macaques and in the cerebrospinal fluid of Parkinson\u2019s disease patients

Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to contribute to the motor and non-motor symptoms of Parkinson’s Disease (PD), and to L-DOPA-induced dyskinesia. Besides the main agonist L-glutamate, two other amino acids in the atypical D-configuration, D-serine and D-aspartate, activate NMDARs. In the present work, we investigated the effect of dopamine depletion on D-amino acids metabolism in the brain of MPTP-lesioned Macaca mulatta, and in the serum and cerebrospinal fluid of PD patients. We found that MPTP treatment increases D-aspartate and D-serine in the monkey putamen while L-DOPA rescues both D-amino acids levels. Conversely, dopaminergic denervation is associated with selective D-serine reduction in the substantia nigra. Such decrease suggests that the beneficial effect of D-serine adjuvant therapy previously reported in PD patients may derive from the normalization of endogenous D-serine levels and consequent improvement of nigrostriatal hypoglutamatergic transmission at glycine binding site. We also found reduced D-serine concentration in the cerebrospinal fluid of L-DOPA-free PD patients. These results further confirm the existence of deep interaction between dopaminergic and glutamatergic neurotransmission in PD and disclose a possible direct influence of D-amino acids variations in the changes of NMDAR transmission occurring under dopamine denervation and L-DOPA therapy.

DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease.

L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease.

The highly-selective 5-HT1A agonist F15599 reduces l-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque

l-3,4-dihydroxyphenylalanine (l-DOPA) is the most effective anti-parkinsonian agent available, but upon chronic administration, patients with Parkinson's disease (PD) experience abnormal involuntary movements, dyskinesia. Modulation of serotonin 1A (5-HT1A) receptors is regarded as an effective way to alleviate dyskinesia, yet this approach has been marred by a reduction of the therapeutic effectiveness of l-DOPA. We hypothesised that highly-selective 5-HT1A stimulation might be a way to alleviate dyskinesia without compromising l-DOPA anti-parkinsonian action. F15599 (also known as NLX-101) is a highly-selective 5-HT1A agonist that displays over 1000 × selectivity over off-target receptors. Seven cynomolgus macaques were administered MPTP and developed severe parkinsonism. Following chronic administration of l-DOPA, they developed severe and reproducible dyskinesia. F15599 (0.003, 0.01, 0.03 and 0.1 mg/kg) or vehicle was administered in combination with l-DOPA and its effect on dyskinesia and l-DOPA anti-parkinsonian was assessed. In combination with l-DOPA, F15599 (0.1 mg/kg) reduced the severity of peak-dose dyskinesia, by ≈45% (P < 0.001), compared to l-DOPA alone. F15599 (any dose) had no effect on duration of on-time or motor activity counts compared to l-DOPA alone. F15599 at 0.03 and 0.1 mg/kg significantly reduced duration of on-time with disabling dyskinesia (by ≈49% and ≈71%, P < 0.05 and P < 0.001, respectively). These results suggest that F15599, a highly-selective 5-HT1A receptor agonist, alleviates dyskinesia without exerting a deleterious effect on l-DOPA anti-parkinsonian action.

L-745,870 reduces the expression of abnormal involuntary movements in the 6-OHDA-lesioned rat.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease, but chronic administration is complicated by the development of dyskinesia. We have previously demonstrated that the dopamine D4 receptor antagonist L-745,870 reduces the severity of L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque without compromising L-DOPA antiparkinsonian benefits. In the current study, we have addressed the effects of L-745,870 on the expression of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine-lesioned rat. Rats were primed with repeated L-DOPA administration, after which acute challenges of L-DOPA/L-745,870 (vehicle, 0.1, 0.3 and 1 mg/kg) were administered, and AIMs were assessed. Rotarod performance and AIMs were assessed. In L-DOPA-primed rats, L-745,870 (1 mg/kg, but not lower doses) alleviated previously established AIMs (by 84%, P<0.001). Whereas rotarod performance was significantly improved by L-DOPA/vehicle treatment, L-DOPA/L-745,870 failed to improve rotarod performance (P>0.05), suggesting that, in contrast to the MPTP-lesioned macaque, L-745,870 reduces L-DOPA antiparkinsonian benefit in the rat model. Overall, these data suggest that L-745,870 may have a narrow therapeutic window as an antidyskinetic agent in advanced Parkinson's disease.

Famotidine, a Histamine H2 Receptor Antagonist, Does Not Reduce Levodopa‐Induced Dyskinesia in Parkinson's Disease: A Proof‐of‐Concept Study

The neural mechanisms underlying levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) may involve histamine (H2) receptors on striatopallidal pathways. We recently demonstrated that the clinically available oral histamine H2 receptor antagonist (H2 RA), famotidine, can reduce l-dopa-induced chorea in MPTP-lesioned macaques. We hypothesized that famotidine may be useful in the treatment of LID in PD patients. We performed a proof-of-concept, double-blind, randomized, multiple cross-over (4×) trial. Seven PD subjects with bothersome dyskinesia were randomized to oral famotidine 80, 120, and 160mg/day and placebo. Each subject was randomized to receive each of the four treatment phases for 14days followed by a 7-day wash-out period between each treatment phase. The primary outcome measure was change in the Unified Dyskinesia Rating Scale (UDysRS; part III) between placebo and famotidine. Secondary outcomes were UDysRS (parts I and II), Global Impression of Change, Lang-Fahn Activities of Daily Living Dyskinesia Scale, Unified Parkinson's Disease Rating part III, and adverse events (AEs). Outcomes were evaluated pre- and post-treatment per dose and analyzed using a mixed-effects linear model. There was no significant effect of famotidine treatment on any of the primary or secondary outcome measures compared to placebo (each dose and all doses combined). There were no significant AEs. Even though the sample size of the current study is limited, famotidine seems to be safe in patients with PD and LID, but showed no potential as an antidyskinetic agent.

Gait Disorders in Parkinsonian Monkeys with Pedunculopontine Nucleus Lesions: A Tale of Two Systems

Gait and balance disorders unresponsive to dopaminergic drugs in Parkinson's disease (PD) are secondary to lesions located outside the dopaminergic system. However, available animal models of PD fail to display l-3,4-dihydroxyphenylalanine (DOPA)-responsive parkinsonism and drug-resistant gait and balance disorders, and this lack of appropriate model could account for the deficit of efficient treatments. Because the pedunculopontine nucleus (PPN) plays an important role in locomotion control, we conducted the present study to investigate the consequences of combined dopaminergic and PPN lesions in a same animal. We used macaques that received first 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to render them parkinsonian and then local stereotaxic lesion of the PPN. Adding bilateral PPN lesions in MPTP-lesioned macaques induced dopamine-resistant gait and balance disorders but unexpectedly improved hypokinesia. Additional MPTP injections resulted in the association of a severe DOPA-responsive parkinsonism together with DOPA-unresponsive gait disorders. Histological examination assessed a severe dopaminergic degeneration and a significant loss of PPN cholinergic neurons. We observed similar results in aged monkeys intoxicated with MPTP: they developed severe DOPA-responsive hypokinesia and tremor together with unresponsive gait and balance disorders and displayed dopaminergic lesion and a weak but significant cholinergic PPN lesion. Our results highlight the complex role of the cholinergic PPN neurons in the pathophysiology of PD because its lesion induces a dual effect with an improvement of hypokinesia contrasting with a worsening of DOPA-unresponsive gait and balance disorders. Thus, we obtained a primate model of PD that could be useful to test symptomatic treatments for these heavily disabling symptoms.

L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease

ObjectiveThe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of l-3,4-dihydroxyphenylalanine (l-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single l-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma l-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients. MethodsWe administered acute challenges of l-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of l-DOPA using high-performance liquid chromatography–mass spectrometry/mass spectrometry. ResultsThe maximal plasma concentration of l-DOPA (Cmax) was 18.2 ± 3.8 nmol/ml and was achieved 1.6 ± 0.3 h after administration (tmax). Half-life was 58.8 ± 22.7 min. l-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 ± 0.7 μg/g tissue protein while they were 1.5 ± 0.1 nmol/ml in the CSF. ConclusionsAlthough therapeutically-active doses of l-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to l-DOPA Cmax similar to those achieved with 200 mg l-DOPA in clinic. l-DOPA tmax and half-life are also similar to those reported in human.

Regulation of cortical and striatal 5-HT1A receptors in the MPTP-lesioned macaque

Serotonergic 1A (5-HT(1A)) receptor agonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in Parkinson's disease (PD), though the mechanism(s) and site(s) of action remain unclear. We employed [(3)H]-WAY 100,635 autoradiographic receptor binding to measure 5-HT(1A) receptor levels in 4 groups of macaques: normal (vehicle-vehicle); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, without exposure to L-DOPA, i.e., untreated parkinsonian (MPTP-vehicle); MPTP-lesioned, receiving a single administration of L-DOPA to alleviate parkinsonism (MPTP-L-DOPA-acute); and MPTP-lesioned, chronically treated with L-DOPA, parkinsonism alleviated but exhibiting dyskinesia (MPTP-L-DOPA-chronic). We demonstrate that 5-HT(1A) receptor binding decreases (by 10%-20%, p < 0.05) in the external layers, but increases (by 80%-100%, p < 0.05) in the middle layers, of the premotor and motor cortex of all MPTP-lesioned macaques. In the striosomes of the caudate nucleus, 5-HT(1A) receptor binding increases in MPTP-vehicle macaques (by 50%, p < 0.05), compared with normal macaques. While 5-HT(1A) receptor binding is low in the matrix of the caudate nucleus in normal macaques, it increases (by 200%, p < 0.05) in MPTP-L-DOPA-chronic macaques. These data suggest that 5-HT(1A) receptors are involved in the pathophysiology of both parkinsonism and complications of L-DOPA therapy.

The α2 adrenergic antagonist fipamezole improves quality of levodopa action in Parkinsonian primates

Reduction in the antiparkinsonian benefit of levodopa is a major complication of long-term levodopa treatment in advanced Parkinson's disease (PD). Such loss of benefit arises because of reduced duration of action and appearance of disabling dyskinesia. We assess the potential of the α(2) adrenergic antagonist fipamezole to reduce motor complications in parkinsonian macaques. MPTP-lesioned macaques were treated acutely with fipamezole (10 mg/kg) alone and in combination with two doses of levodopa. Fipamezole extended both duration and quality of antiparkinsonian action of levodopa. Duration of antiparkinsonian action, on time, was increased by up to 75% while "good-quality" on time, i.e., that not associated with disabling dyskinesia, was increased by up to 98%. Combination of fipamezole with the lower dose of levodopa provided antiparkinsonian benefit at least equivalent to that provided by the higher dose levodopa alone. However, with the combination, antiparkinsonian benefit was of much better quality. The proportion of on time without disabling dyskinesia (79%) was significantly greater than that with high dose levodopa alone (45%). Increased duration and quality of levodopa action may represent therapeutically valuable actions of α(2) adrenergic antagonists.

5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with L-DOPA

Long-term L-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease (PD) is associated with motor complications such as dyskinesia. There are clear functional interactions between dopaminergic and serotonergic type 2A receptors (5-HT(2A))-mediated neurotransmission. Moreover, 5-HT(2A) receptor antagonists can reduce L-DOPA-induced dyskinesia (LID). We hypothesized that enhanced 5-HT(2A)-mediated neurotransmission may be involved in the genesis of L-DOPA-induced dyskinesia. Radioligand binding autoradiography, using [(3)H]-ketanserin, was performed to define 5-HT(2A) receptor levels in brain tissue from macaques: 6 normal; 5 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, parkinsonian macaques, without exposure to L-DOPA; 6 MPTP-lesioned, parkinsonian macaques, receiving a single administration of L-DOPA, and exhibiting no dyskinesia; and 6 MPTP-lesioned, parkinsonian, macaques chronically treated with L-DOPA, and exhibiting dyskinesia. 5-HT(2A) receptor binding was increased in the caudate, putamen, and middle layers of the motor cortex in chronically L-DOPA-treated animals, by 50%, 50%, and 45% respectively, compared with normal macaques. 5-HT(2A) binding was not significantly altered in parkinsonian, untreated, or parkinsonian, single treatment, nondyskinetic macaques, compared with normal. These data provide an anatomical basis for mechanisms to explain the efficacy of 5-HT(2A) antagonists against dyskinesia.

Gene expression profiling in progressively MPTP-lesioned macaques reveals molecular pathways associated with sporadic Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of midbrain dopaminergic neurons. To gain an insight into the mechanisms underlying the progression of PD, gene expression analysis was performed using two different brain regions, the substantia nigra pars compacta (SN) and the striatum (STR), of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkey model of PD. 230 genes were differentially expressed in the MPTP-treated SN compared to control, whereas 452 genes showed altered expression in the MPTP-treated STR, implying that MPTP elicits more damages in the striatal gene expression than in the SN. Comparative data analysis of the transcription profiles on the PD patients and MPTP monkey models, and pathway analysis indicated several signaling pathways as possible routes to MPTP-induced neurodegeneration. Interestingly, the networks which associated with cytoskeletal stability, ubiquitin–proteasome system (UPS) and Wnt signaling gained prominence in our study. Further transcriptional regulatory network analysis suggested the association of the neuronal repressor REST (RE1-silencing transcription factor; NRSF) and androgen receptor with the dysregulation of the striatal genes. Our study suggests the possibility that the dysfunction of multi-network signaling may induce abnormalities in a diverse range of biological processes, such as synaptic function, cytoskeletal stability, survival and differentiation.

P2.201 PYM50028 (Cogane™) is a small molecule inducer of GDNF and BDNF that reverses behavioural impairment in MPTP-lesioned macaques

P2.201 PYM50028 (Cogane™) is a small molecule inducer of GDNF and BDNF that reverses behavioural impairment in MPTP-lesioned macaques

Striatal delta opioid receptor binding in experimental models of Parkinson's disease and dyskinesia

Enhanced delta opioid receptor transmission may represent an endogenous compensatory mechanism in parkinsonism to reduce the activity of the indirect striatopallidal pathway following dopamine depletion. Furthermore, increased delta opioid receptor transmission may be causative in the production of dyskinesia following repeated dopaminergic treatment in Parkinson's disease. The present study employed radioligand receptor autoradiography, using [3H]naltrindole, a ligand selective for the delta opioid receptor, to assess delta opioid receptor binding sites in forebrain regions of reserpine-treated rats, and in parkinsonian nondyskinetic, and dyskinetic MPTP-lesioned macaques. In reserpine-treated animals, specific delta opioid binding was increased in premotor cortex (+30%), sensorimotor striatum (+20%), and associative striatum (+17%) rostrally, but was not changed in caudal forebrain. In contrast, delta opioid receptor binding was not significantly altered at any region analyzed, in either nondyskinetic or dyskinetic, MPTP-lesioned macaques, compared to normal. These results suggest that transient changes in delta opioid receptor binding may occur in motor circuits following acute dopamine depletion. However, in the more chronic MPTP-lesioned macaque model, simple changes in delta opioid receptor number or affinity are unlikely to contribute to mechanisms for abnormal opioid transmission in Parkinson's disease and dyskinesia.

Unraveling substantia nigra sequential gene expression in a progressive MPTP-lesioned macaque model of Parkinson's disease

Taking advantage of a progressive nonhuman primate model mimicking Parkinson's disease (PD) evolution, we monitored transcriptional fluctuations in the substantia nigra using Affymetrix microarrays in control (normal), saline-treated (normal), 6 days-treated (asymptomatic with 20% cell loss), 12 days-treated (asymptomatic with 40% cell loss) and 25 days-treated animals (fully parkinsonian with 85% cell loss). Two statistical methods were used to ascertain the regulation and real-time quantitative PCR was used to confirm their regulation. Surprisingly, the number of deregulated transcripts is limited at all time points and five clusters exhibiting different profiles were defined using a hierarchical clustering algorithm. Such profiles are likely to represent activation/deactivation of mechanisms of different nature. We briefly speculate about (i) the existence of yet unknown compensatory mechanisms is unraveled, (ii) the putative triggering of a developmental program in the mature brain in reaction to progressing degeneration and finally, (iii) the activation of mechanisms leading eventually to death in final stage. These data should help development of new therapeutic approaches either aimed at enhancing existing compensatory mechanisms or at protecting dopamine neurons.

Increased striatal pre-proenkephalin B expression is associated with dyskinesia in Parkinson’s disease

Long-term treatment of Parkinson’s disease with levodopa is compromised by the development of motor complications, including on–off fluctuations and involuntary movements termed dyskinesia. The neural mechanisms underlying treatment-related dyskinesias may involve underactivity of the output regions of the basal ganglia, i.e., the medial segment of the globus pallidus (GPm) and substantia nigra pars reticulata (SNR). Increased activity of GABAergic neurons of the “direct” striatopallidal pathway has been implicated in the suppression of the GPm and SNR and thus the development of dyskinesia. The direct pathway uses opioids as a co-neurotransmitter. These opioid peptides are products of the high-molecular weight opioid precursor pre-proenkephalin B (PPE-B). In situ hybridisation studies were employed to investigate PPE-B mRNA expression in postmortem striatal tissue from patients with a clinicopathological diagnosis of Parkinson’s disease, all of whom displayed levodopa-induced motor complications, including dyskinesia prior to death and in the caudate-putamen (striatum) of the MPTP-lesioned macaque model of Parkinson’s disease with treatment-related dyskinesia. Striatal PPE-B mRNA expression was significantly increased by 172% in dyskinetic Parkinson’s disease patients compared to age-matched controls. This increase was heterogeneous with increased expression within the striosomes compared to matrix compartments of the striatum. Striatal PPE-B mRNA expression was significantly increased by 185% in the MPTP-lesioned macaque exhibiting dyskinesia, compared to parkinsonian, nondyskinetic MPTP-lesioned macaques, and by 146% compared to non-parkinsonian, nondyskinetic controls. Increased PPE-B mRNA expression, with subsequent elevations in opioid peptide transmission within the direct striatal output pathways, may underlie treatment-related dyskinesia in Parkinson’s disease.

Striatal AMPA Receptor Binding Is Unaltered in the MPTP-Lesioned Macaque Model of Parkinson's Disease and Dyskinesia

Long-term levodopa or dopamine agonist treatment in the MPTP-lesioned primate model of Parkinson's disease elicits dyskinesia, which is phenotypically similar to levodopa-induced dyskinesia in patients with Parkinson's disease. AMPA receptor antagonists have previously been shown to have both anti-parkinsonian and anti-dyskinetic actions in MPTP-lesioned primates, suggesting that AMPA receptor transmission is functionally overactive under these conditions. In this study, we investigated the level of striatal AMPA receptor binding in the MPTP lesioned primate using the selective AMPA ligand 3H-(S)-5-fluorowillardiine. AMPA receptor binding was studied in nonparkinsonian, nondyskinetic parkinsonian, and dyskinetic macaques. Striatal AMPA receptor binding was not different in any of the treatment groups (P > 0.05). Although AMPA receptor-mediated transmission is functionally overactive in Parkinson's disease and dyskinesia, changes in striatal AMPA receptor levels are not likely to be the cause of such movement disorders.