Changes in brain catecholamines and dopamine uptake sites at different stages of MPTP parkinsonism in monkeys

Alexander, Guilermo M.; Schwartzman, Robert J.; Brainard, Laine; Gordon, Susan J.; Grothusen, John R.

doi:10.1016/0006-8993(92)91584-2

Cited by 50 publications

(30 citation statements)

References 20 publications

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“…The data reported here demonstrate that binding of [ 3 H]GBR12935 in the caudate and putamen of MPTP-lesioned monkeys reflects the decrease in DAergic innervation as observed by DA content. A similar striatal decrease of DAT binding sites (approximately 90%) labeled with [ 3 H]mazindol was previously reported (Alexander et al, 1992;Gnanalingham et al, 1995). Our study and previous reports are consistent with the changes seen in the MPTP-lesioned monkey where the nigro-striatal DAergic neurons demonstrated marked cell loss (Kish et al, 1988;Parent and Lavoie, 1993).…”

Section: Discussionsupporting

confidence: 93%

“…The loss of DA and DAergic neurons in Parkinson's disease is accompanied by a matching loss in DAT localized on nerve endings in the striatum (Janowsky et al, 1987;Maloteaux et al, 1988;Miller et al, 1997). MPTP parkinsonism in primates also results in the loss of DAT sites in the striatum (Alexander et al, 1992;Fischman et al, 1997;Gnanalingham et al, 1995). Hence, this transporter is useful to determine the extent of denervation.…”

Section: Introductionmentioning

confidence: 94%

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Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Goulet

Morissette

Grondin

et al. 1999

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The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was investigated. The MPTP lesion induced a marked depletion of DA (90% or more vs. control) in the caudate nucleus and putamen. The densities of NT agonist binding sites labeled with [125I]NT and the NT antagonist binding sites labeled with [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys. Levocabastine did not compete with high affinity for [125I]NT binding in the monkey cingulate cortex, suggesting that only one class of NT receptors was labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding sites (-92% vs. Control) was observed in the striatum of MPTP-monkeys and an important loss of DAT mRNA(-86% vs. Control) was observed in substantia nigra. Treatments for 1 month with either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT and DAT binding sites or DAT mRNA levels. The decrease of striatal NT binding sites was less than expected from the decrease of DA content in this nucleus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervation, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 94%

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Goulet

Morissette

Grondin

et al. 1999

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“…In control primates, using the high sensitivity of the increased relaxivity with iron oxide nanoparticles (IRON) technique (Mandeville et al, 1998; Y. C. Chen et al, 2001), we were able to observe distinct regional activation by amphetamine at a much higher resolution than any previous in vivo techniques. In parkinsonian primates, we could determine the effects of selective DA denervation and the relative sparing of regions innervated by the A10 neurons, previously only described using postmortem histology (Chiueh et al, 1985;Schneider et al, 1987;Alexander et al, 1992;German et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging

Jenkins¹,

Sánchez‐Pernaute²,

Brownell³

et al. 2004

J. Neurosci.

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Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2␤-carbomethoxy-3␤-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates.

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“…If this were the case, a larger response might be expected in animals with only mild/moderate damage, presumably because there would be more remaining presynaptic terminals (Levant, 1997). Conversely, a small or negligible response might be anticipated when the dopamine terminals are severely reduced (Alexander et al, 1992;Quik et al, 2001). In fact, in the earlier study, the animals exhibited moderate parkinsonism .…”

Section: Discussionmentioning

confidence: 78%

Effect of the D3 Dopamine Receptor Partial Agonist BP897 [N-[4-(4-(2-Methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on l-3,4-Dihydroxyphenylalanine-Induced Dyskinesias and Parkinsonism in Squirrel Monkeys

Hsu

Togasaki²,

Bézard³

et al. 2004

J Pharmacol Exp Ther

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Although L-3,4-dihydroxyphenylalanine (L-dopa) is one of the most effective therapies for Parkinson's disease, continued treatment may result in excessive involuntary movements known as L-dopa-induced dyskinesias (LIDs). Because LIDs can become dose-limiting, there is great interest in finding ways to ameliorate or prevent this troubling side effect of L-dopa therapy. It was recently reported that the D3 receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] reduces LIDs without diminishing antiparkinsonian effects of L-dopa in macaques. In the present study, we tested the effects of BP897 on LIDs in squirrel monkeys, a nonhuman primate particularly prone to dyskinesias. Parkinsonism was induced using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Animals were then gavaged with L-dopa/carbidopa (7.5 or 15 mg/kg/dose) without and with BP897. The effects of BP897 treatment were evaluated on several components of LIDs, including time course, peak dyskinesias, and area under the curve (AUC), a measure that encompasses both peak and duration of the response. Analyses of the time course and overall dyskinetic response (AUC) showed that BP897 significantly reduced LIDs but at the expense of the antiparkinsonian effect of L-dopa. BP897 had no significant effect on peak dyskinesias. Correlation studies showed that beneficial effects of BP897 on dyskinesias were linked to a decline in the antiparkinsonian action of L-dopa. Analyses of a subgroup of animals with mild/moderate parkinsonism yielded comparable results. Thus, in squirrel monkeys in contrast to macaques, BP897 fails to exert an antidyskinetic effect without diminishing the antiparkinsonian effects of L-dopa. These results suggest that BP897 may be less effective than originally anticipated for treating LIDs in Parkinson's disease.

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Changes in brain catecholamines and dopamine uptake sites at different stages of MPTP parkinsonism in monkeys

Cited by 50 publications

References 20 publications

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Neurotensin receptors and dopamine transporters: Effects of MPTP lesioning and chronic dopaminergic treatments in monkeys

Mapping Dopamine Function in Primates Using Pharmacologic Magnetic Resonance Imaging

Effect of the D3 Dopamine Receptor Partial Agonist BP897 [N-[4-(4-(2-Methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on l-3,4-Dihydroxyphenylalanine-Induced Dyskinesias and Parkinsonism in Squirrel Monkeys

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