Behavioral changes are not directly related to striatal monoamine levels, number of nigral neurons, or dose of parkinsonian toxin MPTP in mice

Rousselet, Estelle; Joubert, Charles; Crinon, Jacques; Parain, Karine; Tremblay, Léon; Orieux, Gaël; Launay, Jean‐Marie; Cohen-Salmon, Charles; Hirsch, Étienne C.

doi:10.1016/s0969-9961(03)00108-6

Cited by 89 publications

(78 citation statements)

References 49 publications

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“…When the DA system is lesioned with MPTP, the small number of DA neurons that are spared have a compensatory increase in activity, resulting in normal or even elevated DA turnover [as measured by dihydroxyphenylacetic acid (DOPAC) levels and DA/DOPAC ratio] despite fewer terminals (Table 1) (26,27). By contrast, because NE is required for DA-neuron firing and DA release, NEdeficient animals (DbhϪ/Ϫ mice or DSP4-lesioned animals) have very low extracellular DA levels, despite normal tissue DA content in the striatum (12,24).…”

Section: Discussionmentioning

confidence: 99%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

172

115

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Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine ␤-hydroxylase knockout (Dbh؊/؊) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh؊/؊ mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh؊/؊ mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh؊/؊ mice. Finally, striatal levels of phospho-ERK-1/2 and ⌬FosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh؊/؊ mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.dopamine ͉ Parkinson's disease ͉ dyskinesias ͉ dopamine ␤-hydroxylase P arkinson's disease (PD) affects Ϸ1% of the world's aging population (1). Despite this high prevalence and intensive research into its origins, the etiology of PD remains largely unknown. The disease is characterized by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN), and symptoms, which tend to manifest when Ϸ80% of striatal DA is lost, include bradykinesia, postural instability, rigidity, and resting tremor. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, is known to produce parkinsonism in humans and causes severe DA loss in animals (2). Because of its ability to recapitulate the neuropathology of PD, MPTP is used widely in PD research. However, MPTP has been unable to reliably reproduce the motor symptoms of PD in mice, which limits the utility of MPTP-treated mice as an animal model of the disease (3). Differences in mouse strain and experimental paradigms may at least partially account for these inconsistencies.Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4-6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may a...

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Section: Discussionmentioning

confidence: 99%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

172

115

View full text Add to dashboard Cite

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“…Nevertheless, more sensitive measures, such as gait analysis, or the pole or grid tests, have been able to detect DA loss as low as 50% [89]. Unfortunately, motor deficits do not correlate well with the degree of DA neuronal loss, striatal DA levels or the dose of MPTP [101].…”

Section: Pd Models: Acute or Chronic Delivery Of Neurotoxicantsmentioning

confidence: 99%

Animal models of Parkinson’s disease progression

Sonsalla²,

2008

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Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is not understood. This disease occurs both sporadically and through inheritance of single genes, although the familial types are rare. Over the past decade or so, experimental and clinical data suggest that PD could be a multifactorial, neurodegenerative disease that involves strong interactions between the environment and genetic predisposition. Our understanding of the pathophysiology and motor deficits of the disease relies heavily on fundamental research on animal models and the last few years have seen an explosion of toxin-, inflammation-induced and genetically manipulated models. The insight gained from the use of such models has strongly advanced our understanding of the progression and stages of the disease. The models have also aided the development of novel therapies to improve symptomatic management, and they are critical for the development of neuroprotective strategies. This review critically evaluates these in vivo models and the roles they play in mimicking the progression of PD.

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“…MPTP was used as a validated model of PD. Rousselet et al have previously shown that MPTP-treated mice exhibit loss of dopaminergic neurons and dopamine content (20). In their study, they did not evidence any failure in intoxication.…”

Section: Discussionmentioning

confidence: 58%

“…This experimental model was previously validated by Rousselet et al (20) who showed that MPTP injections led to a loss of nigral dopaminergic neurons, a reduction in striatal dopamine content and a behavioural disturbance. As reported by the authors, in this murine model, all animals exhibit an homogeneous and severe loss (90%) of dopamine content (20). All experiences were conducted on day 7, since MPTP and metabolites were completely excreted and neurotoxicity by close contact was void (21).…”

Section: Acute Mptp Intoxication Protocolmentioning

confidence: 86%

Role of Two Efflux Proteins, ABCB1 and ABCG2 in Blood-Brain Barrier Transport of Bromocriptine in a Murine Model of MPTP-Induced Dopaminergic Degeneration

et al. 2009

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-Purpose. MPTP-induced dopaminergic degeneration is an experimental model commonly used to explore Parkinson's disease. Cerebral drug transport by ABC transporters in MPTP models has never been reported. We have investigated the role of ABCB1 and ABCG2 on the bromocriptine transport through the blood-brain barrier (BBB) in a murine MPTP model. Methods. The bromocriptine transport was investigated by measuring brain and plasma concentrations of bromocriptine after ip administration in MPTP mice. The BBB integrity was controlled by measuring the brain vascular volume of two vascular space markers, [

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Behavioral changes are not directly related to striatal monoamine levels, number of nigral neurons, or dose of parkinsonian toxin MPTP in mice

Cited by 89 publications

References 49 publications

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Animal models of Parkinson’s disease progression

Role of Two Efflux Proteins, ABCB1 and ABCG2 in Blood-Brain Barrier Transport of Bromocriptine in a Murine Model of MPTP-Induced Dopaminergic Degeneration

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