Brain monoamines and parkinsonism.

Hornykiewicz, O

doi:10.1037/e472122004-001

Cited by 58 publications

(58 citation statements)

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“…We observed a massive decrease in striatal DA, DOPAC, and HVA concentrations, as reported in parkinsonian patients postmortem (Hornykiewicz, 1975;Agid et al, 1987;Calon et al, 2003) and MPTP monkeys (Elsworth et al, 1987(Elsworth et al, , 2000Pifl et al, 1991). These decreases are consistent with major dopaminergic fiber losses, greater in the sensorimotor than in the associativelimbic territory (Mounayar et al, 2007).…”

Section: Modifications Associated With Motor Symptom Expressionsupporting

confidence: 86%

“…However, most concern striatal dysfunction after the onset of motor symptoms and are limited to determinations of the concentrations of DA, glutamate (Glu) and GABA only. It is thus well established in humans (Hornykiewicz, 1975(Hornykiewicz, , 1998Agid et al, 1987) and in animal models of the disease, such as 6-hydroxydopamine (6-OHDA)-lesioned rats (Hefti et al, 1980;Schwarting and Huston, 1996) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (Elsworth et al, 1989;Skirboll et al, 1990;McCallum et al, 2006), that the motor symptom state of PD is characterized by a large decrease in levels of DA and its metabolites and an increase in DOPAC/DA and homovanillic acid (HVA)/DA ratios. Increases in striatal concentrations of Glu and GABA have also been reported in humans (Kish et al, 1988;Hornykiewicz, 2001), 6-OHDA rats (Lindefors and Ungerstedt, 1990;Meshul et al, 1999;Bruet et al, 2003), and MPTP monkeys (Robinson et al, 2003).…”

Section: Introductionmentioning

confidence: 98%

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Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis

Boulet

Mounayar²,

Poupard³

et al. 2008

J. Neurosci.

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Parkinson's disease (PD) patients express motor symptoms only after 60 -80% striatal dopamine (DA) depletion. The presymptomatic phase of the disease may be sustained by biochemical modifications within the striatum. We used an appropriate specific 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model (Mounayar et al., 2007) to study the compensatory mechanisms operating in recovery from PD motor symptoms. We assessed the levels of DA and its metabolites (DOPAC, homovanillic acid), GABA, glutamate (Glu), serotonin (5-HT) and its metabolite (5HIAA) by repeated intracerebral microdialysis in awake animals before exposure to MPTP during full expression of the motor symptoms induced by MPTP and after recovery from these symptoms. Measurements were obtained from two functionally and anatomically different striatal areas: the associative-limbic territory and sensorimotor territory. Animals with motor symptoms displayed an extremely large decrease in levels of DA and its metabolites and an increase in Glu and GABA levels, as reported by other studies. However, we show here for the first time that serotonin levels increased in these animals. We found that increases in DA levels in the sensorimotor and/or associative-limbic territory and high levels of 5-HT and of its metabolite, 5HIAA, were associated with recovery from motor symptoms in this model. Determining whether similar changes in DA and 5-HT levels are involved in the compensatory mechanisms delaying the appearance of motor symptoms in the early stages of PD might make it possible to develop new treatment strategies for the disease.

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Section: Modifications Associated With Motor Symptom Expressionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 98%

Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis

Boulet

Mounayar²,

Poupard³

et al. 2008

J. Neurosci.

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“…This neurodegenerative movement disorder is characterized by declines in dopaminergic cell bodies in the substantia nigra and nerve terminals in the striatum (Davidson et al, 1971;Hornykiewicz, 1975;Olanow, 2004;Samii et al, 2004;Savitt et al, 2006). Because nAChRs are present on striatal dopaminergic terminals, these receptors are correspondingly decreased in experimental models of nigrostriatal damage and Parkinson's disease (Quik, 2004).…”

mentioning

confidence: 99%

Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2^* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum

Bordia¹,

Grady²,

McIntosh³

et al. 2007

Mol Pharmacol

126

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Parkinson's disease is a neurodegenerative movement disorder characterized by a loss of substantia nigra dopamine neurons, and corresponding declines in molecular components present on striatal dopaminergic nerve terminals. These include the ␣6␤2* nicotinic acetylcholine receptors (nAChRs), which are localized exclusively on dopamine terminals in striatum (*denotes the presence of possible additional subunits). In this study, we used a novel ␣-conotoxin MII (␣-CtxMII) analog E11A to further investigate ␣6␤2* nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with 125 I-␣-CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct ␣6␤2* nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with ϳ40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in ␣4 nAChR-null mutant mice. Because 125 I-␣-CtxMII binds primarily to ␣6␣4␤2␤3 and ␣6␤2␤3 nAChR subtypes in mouse striatum, these data suggest that the population lost in the ␣4 knockout mice was the ␣6␣4␤2␤3 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal ␣6␤2* populations in two animal models and in Parkinson's disease. There was a preferential loss of the very high affinity subtype in striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), monkeys treated with MPTP, and patients with Parkinson's disease. These data suggest that dopaminergic terminals expressing the ␣6␣4␤2␤3 population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with ␣-CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.

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“…While classical PD motor deterioration involves the gradual degeneration of the dopaminergic nigrostriatal pathways (DNPs) [15][16][17], prodromal signs are increasingly being documented in individuals that subsequently develop the more classic disease. The progressive clinical picture of PD was defined by Hoehn and Yahr in 1967 (stages I-IV, with stage V being bedridden and totally disabled) [18] and continues to be in use today.…”

Section: Introductionmentioning

confidence: 99%

Can population genomics guide future therapeutic gene transfer strategies for Parkinson’s disease?

Fiandaca¹,

Padilla²,

Conteh³

et al. 2013

OJGen

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Brain monoamines and parkinsonism.

Cited by 58 publications

References 0 publications

Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis

Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis

Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2^* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum

Can population genomics guide future therapeutic gene transfer strategies for Parkinson’s disease?

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Brain monoamines and parkinsonism.

Cited by 58 publications

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Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis

Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis

Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum

Can population genomics guide future therapeutic gene transfer strategies for Parkinson’s disease?

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Nigrostriatal Damage Preferentially Decreases a Subpopulation of α6β2^* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum