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Parkinson’s Disease: Animal Models
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DOI: 10.1016/B978-0-12-374105-9.00221-5
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Porras G, Fernagut P -O and Bezard E (2010) Parkinson’s Disease: Animal
Models. In: Kompoliti K, and Verhagen Metman L (eds.) Encyclopedia of
Movement Disorders, vol. 3, pp. 420-424 Oxford: Academic Press.
Author's personal copy
420
Parkinson’s Disease: Animal Models
PD. Despite the association with vascular lesions, the
underlying pathophysiology is poorly understood. Further research priorities include validating diagnostic criteria and diagnostic assessments, and rigorous evaluation
of risk modification and potential therapeutic options for
this increasingly common syndrome.
See also: Akinetic-Rigid Syndrome; Binswanger’s Subcortical Arteriosclerotic Encephalopathy; Bradykinesia;
Dementia, Movement Disorders; Gait Disturbances in
Parkinsonism; Levodopa; Neuroimaging, Parkinson’s
Disease; Parkinson’s Disease: Definition, Diagnosis,
and Management; Progressive Supranuclear Palsy;
Rigidity; SPECT Imaging in Movement Disorders.
Further Reading
Bennett DA, Beckett LA, Murray AM, et al. (1996) Prevalence of
parkinsonian signs and associated mortality in a community
population of older people. New England Journal of Medicine 334(2):
71–76.
Huang Z, Jacewicz M, and Pfeiffer RF (2002) Anticardiolipin antibody in
vascular parkinsonism. Movement Disorders 17: 992–997.
Jellinger KA (2003) Prevalence of cerebrovascular lesions in Parkinson’s
disease: A postmortem study. Acta Neuropathologica 105:
415–419.
Lorberboym M, Djaldetti R, Melamed E, Sadeh M, and Lampl Y (2004)
123
I-FP-CIT SPECT imaging of dopamine transporters in patients
with cerebrovascular disease and clinical diagnosis of vascular
parkinsonism. Journal of Nuclear Medicine 45: 1688–1693.
Peralta C, Werner P, Holl B, et al. (2004) Parkinsonism following striatal
infarcts: Incidence in a prospective stroke unit cohort. Journal of
Neural Transmission 111: 1473–1483.
Peters S, Eising EG, Przuntek H, and Muller T (2001) Vascular
parkinsonism: A case report and review of the literature. Journal of
Clinical Neuroscience 8: 268–271.
Rampello L, Alvano A, Battaglia G, et al. (2005) Different clinical and
evolutional patterns in late idiopathic and vascular parkinsonism.
Journal of Neurology 252: 1045–1049.
Rektor I, Rektorova I, and Kubova D (2006) Vascular parkinsonism – An
update. Neurological Sciences 248: 185–191.
Thanvi B, Lo N, and Robinson T (2005) Vascular parkinsonism – An
important cause of parkinsonism in older people. Age and Ageing 34:
114–119.
Tolosa E, Wenning G, and Poewe W (2006) The diagnosis of Parkinson
disease. Lancet Neurology 5: 75–86.
Van Zagten M, Lodder J, and Kessels F. Gait disorder and parkinsonian
signs in patients with stroke related to small deep infarcts and white
matter lesions. Movement Disorders 13: 89–95.
Winikates J and Jankovic J (1999) Clinical correlates of vascular
parkinsonism. Archives of Neurology 56: 98–102.
Zijlmans JCM, Daniel SE, Hughes AJ, Revesz T, and Lees AJ (2004)
Clinicopathological investigation of vascular parkinsonism, including
clinical criteria for diagnosis. Movement Disorders 19: 630–640.
Zijlmans JCM, Katzenschlager R, Daniel SE, and Lees AJ (2004) The
L-dopa response in vascular parkinsonism. Journal of Neurology,
Neurosurgery and Psychiatry 75: 545–547.
Zijlmans JCM, Thijssen HOM, Vogels OJM, et al. (1995) MRI in patients
with suspected vascular parkinsonism. Neurology 45: 2183–2188.
Parkinson’s Disease: Animal Models
G Porras, P-O Fernagut, and E Bezard, Université Victor Segalen Bordeaux 2, Bordeaux, France
ã 2010 Elsevier Ltd. All rights reserved.
Introduction
Glossary
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) – A neurotoxin that kills cathecholaminergic
neurons with a greater efficacy upon dopamine
neurons. It is used for producing mouse and primate
models of Parkinson’s disease.
Lewy bodies – Pathological intracytoplasmic
hallmark of Parkinson’s disease that is an
a-synuclein positive inclusion.
a-synuclein – Presynaptic protein which
accumulation and mutations are associated with
increased risk of Parkinson’s disease. It was further
shown to be the main component of the Lewy bodies;
Rotenone/paraquat – Pesticides blocking the
mitochondrial respiratory chain used for modeling
Parkinson’s disease in animals. Suspected of acting
as environmental toxins.
Parkinson’s disease (PD) is a progressive neurodegenerative
disorder, affecting 1% of the population over 55. This
pathology is primarily characterized by a progressive degeneration of the nigrostriatal dopamine (DA) system associated with the presence of intracytoplasmic a-synuclein
positive inclusions known as Lewy bodies. Fully developed,
PD comprises motor impairments, including bradykinesia,
rigidity, tremor, and postural instability.
Whereas the etiology of idiopathic PD is still
unknown, its pathophysiology has rapidly advanced due
to the development of relevant mammalian models. Using
these models, levodopa (L-3,4-dihydroxyphenylalanine
or L-dopa) was first applied to compensate striatal DA
deficiency associated with the motor symptoms of PD.
Unfortunately, although effective in the early stages of
PD, this symptomatic therapy loses efficacy over time due
to the developments of severe side effects known as
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Parkinson’s Disease: Animal Models
levodopa-induced dyskinesia (LID). Experimental models
of PD are thus needed to gain insights into the pathological mechanisms of the disease and to develop new therapeutic strategies. Ideally, for direct relevance to human
PD, a model should have the following characteristics: (1)
a chronically progressive loss of DA neurons, (2) motor
symptoms clearly improved by levodopa treatment,
(3) nonmotor symptoms such as cognitive impairments,
sleep disorders, constipation, orthostatic hypotension, etc.,
(4) development of LID over time, and (5) lewy body
inclusions. However, it is necessary to admit that there
still a long road ahead of us. Some of the available models
allow reproducing at least one or two characteristics of the
disease. Further, some discrepancies exist between neuropathological data obtained in PD patients and data from
experimental models. Indeed, PD is a chronic degenerative
disease, whereas animal models could be produced either
by acute lesion or by semichronic intoxication with specific
neurotoxins. It is clear that we need animal models that will
come closer to the gradual progression of DA neuronal
death and the subsequent evolution of parkinsonian motor
and nonmotor disabilities. Current evidence suggests an
involvement of both environmental and genetic factors in
the progression of PD. Future pathophysiological studies
should take all these factors into account. PD cannot any
longer be studied as a discontinuous pathology, in which the
patient passes suddenly from a normal to a full parkinsonian
state. The following nonexhaustive review looks at reversible pharmacological, toxic and genetic in vivo mammalian
models of PD available today and proposes a brief assessment of their relative merits.
Pharmacological Model
Those models were the first to be developed and are still
in use. Depleting brain stores of monoamines with the
Rauwolfia alkaloid reserpine or administering a neuroleptic,
for example, haloperidol, are two reversible pharmacological models, which induce transient functional disturbances
by a temporary blockade of DA neurotransmission.
The Reserpine Model
It was the first PD animal model. Reserpine, by interfering
with the storage of catecholamine, results in monoamine
depletion in nerve terminals and induces a transient
hypolocomotion with resultant hypokinesia, akinesia,
and even catalepsy.
Most of the available pharmacological studies of
reserpine-induced motor symptoms, focused on rigidity
or the indirect evaluation of hypokinesia. Besides this
model of parkinsonism, several studies have shown that
rats treated with reserpine develop orofacial dyskinesia,
which is considered as a good model of tardive dyskinesia.
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The precise mechanisms underlying the effects of
reserpine treatment have still not been elucidated but it
has been shown that the depletion reaches not only DA
but also the others monoamines. Although the use of this
model has suffered of a certain disaffection due to its
nonselectivity and its transient nature, it provides a useful
tool to investigate the symptomatic antiparkinsonian
activity of new chemical entities featuring DA activity,
a-adrenoreceptor blockers and glutamatergic antagonists.
The Neuroleptic Model
Parkinsonian-like symptoms including akinesia, muscular
rigidity, and tremor were induced by the majority of DA
antagonists both in humans and in experimental models.
Catalepsy, another major early side effect of neuroleptics
is characterized by the inability to change an externally
imposed posture. Numerous studies have investigated
the ability of antiparkinsonian compounds to counteract
neuroleptic-induced catalepsy: DA agonists and levodopa,
anticholinergics Glutamate agents, and GABA antagonists. Most of these studies have been performed on
rodents, very few on nonhuman primates.
Although neuroleptics induce extrapyramidal symptoms
resembling those observed in human PD, their relevance for
animal models of PD is limited. Their action is firstly
transient and reversible. They can block DA transmission
but cannot induce degeneration of DA nigrostriatal neurons.
The applications of this model are therefore limited.
Relevance of Reversible Models
The reserpine and neuroleptic models of PD are not the
only experimental pharmacological models of PD available. Animal models of tremor have also been developed,
such as the model using oxotremorine, a selective cholinergic agonist acting on muscarinic receptors. Further, like
reserpine, striatal DA depletion following administration
of methamphetamine has prompted to propose this psychostimulant as a good candidate to modelling PD. None
of these models, however, reproduce the degenerative
process of PD. They remain relevant for the study of
specific symptoms but cannot provide any further contribution to the development of dynamic animal models
since their transient nature excludes de facto any degenerative evolution and their characteristics do not reproduce exactly the clinical features of human PD.
Neurotoxic Models
Although it is clear that the PD does not result only from
the loss of nigrostriatal DA neuron, the common feature of
all neurotoxin-induced models, namely those produced
broadly by the toxins 6-hydroxydopamine (6-OHDA) or
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),
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Parkinson’s Disease: Animal Models
is that they all induce a massive and reproducible nigrostriatal degeneration.
The 6-Hydroxydopamine Model
For approximately the last 50 years, 6-OHDA has become
the most commonly used model for PD due to its specific
neurotoxic effects on catecholaminergic pathways. The
6-OHDA structural analogy with catecholamines facilitates
its transfer and accumulation through the high-affinity
transport system located on the plasma membrane.
In these monoaminergic neurons, 6-OHDA induces neurodegeneration by oxidative stress through formation of
reactive oxygen species and quinones. Many other mechanisms have been involved since then. To reduce damage on
noradrenergic (NA) neurons which are more sensitive to
6-OHDA than DA neurons, a pretreatment with desimipramine, a selective inhibitor of NA-reuptake injected
systemically, is required. The specificity obtained is still,
however, not absolute, and nonspecific lesions of the serotoninergic or other catecholaminergic systems may occur.
Whereas the rat remains the species of choice, 6-OHDA
is also effective in several other species from zebrafish to
primate confirming that this toxin is a powerful experimental tool. Since the toxin is unable to cross the blood–brain
barrier, 6-OHDA is injected intracerebrally under stereotactic guidance to target the nigrostriatal DA pathway.
Several local approaches were thus considered and toxin
can be administered at the distinct parts of this ascending
DA pathway, uni- or bi-laterally. Following the princeps
work of Ungerstedt who injected 6-OHDA bilaterally into
the rat substantia nigra (SNc), models with bilateral DA
lesion have been proposed. Nevertheless, wherever the
6-OHDA was administered, rats present akinesia, aphagia
and adipsia and mortality increases significantly. More
recent studies have proposed partial bilateral 6-OHDA
lesions, particularly at the striatal level but this model, as
good as it can be, must be a compromise between lack of
induced mortality and sufficient DA depletion. Accordingly,
the most practical and frequent application of the 6-OHDAlesioned model is the unilateral intracerebral injection. This
allows the assessment of rotational behaviour that correlates
well with the degree of lesion, in response to drugs affecting
DA transmission. Several additional motor tests have also
been validated in 6-OHDA rats, including akinesia or LID.
Apart from the testing of a number of antiparkinsonian
compounds, the so-called ‘Ungerstedt model’ has greatly
improved our knowledge of the physiopathology of the
basal ganglia. However, the 6-OHDA model is not able
to replicate many of the neuropathological features of
human PD. It does not alter other brain regions and to date,
the formation of cytoplasmatic inclusions (Lewy bodies) has
never been observed in this model. Further, rotational behaviour, although an interesting criteria for drug discrimination, does not allow estimating all human parkinsonian
symptomatology such as the nonmotor symptoms. Finally,
this acute model does not induce a slow progressive neuronal
death which characterizes the pathophysiology of human
PD, unless when injected into the striatum.
Despite these drawbacks, the stable lesions produced by
the administration of 6-OHDA allow long-term studies.
For this reason, 6-OHDA model has been particularly
useful to quantify motor deficit, develop pharmacological
screening as well as neuroprotective studies by testing cell
transplantation or neurotrophic factors.
The 1-Methyl-4-phenyl1,2,3,6-tetrahydropyridine Model
The MPTP model is probably the best characterized and
most used model of PD at present. In the early 1980s, several
young Californian adults developed a severe parkinsonianlike syndrome after injection of a synthetic heroin contaminated by a meperidine analogue, MPTP. The active metabolite of MPTP, MPP+ was accumulated in DA cells via the
dopamine transporter (DAT) and induced mitochondrial
complex I inhibition causing oxidative stress and cell
death. MPTP induces symptoms virtually identical to
those of idiopathic PD and this syndrome was considerably
improved by the administration of levodopa or DA agents.
As in humans, the administration of MPTP in various
animals has been shown to induce a selective degeneration of the DA nigrostriatal pathway with parkinsonianlike motor impairment. The most obvious impact of
MPTP-based toxin models was the development of primate models, which come the closest to human PD. Rats
remain relatively insensitive to the administration of
MPTP and only specific strains of mice are sensitive to
its action. Further, in comparison to the level that nigral
degeneration obtains in monkeys, MPTP-induced DA
depletion in mice, requires higher dose and permanent
behavioral PD symptoms are rarely noticeable. This led
to use this model for biochemical investigation of the
neurotoxic action of MPTP.
Various doses and regimes of MPTP administration
(route, number and frequency of injections) are used by
different laboratories and can produce varying degrees of
DA loss. The most frequently protocol used for the
MPTP mouse model comprises four injections of MPTP
(20 mg kg 1; intraperitoneally (i.p.)) at 2-h intervals. This
produces a sharp decrease in striatal DA levels and leads
to a loss of DA neurons in the ventral mesencephalon.
Among the various schedules of MPTP intoxication for
primates, toxin could be administered either systemically
(intraperitoneal (i.p.), intravenous (i.v.), intramuscular (i.m.),
or subcutaneous (s.c.)) to achieve a bilateral lesion or through
the carotid on one side when a hemiparkinsonian syndrome
is preferred. In the former model, a supporting therapeutic
trial with levodopa is required to allow MPTP-treated animals to maintain a normal nutrition. The second model has
been useful in electrophysiological studies or for studying
novel antiparkinsonian therapies.
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Parkinson’s Disease: Animal Models
In nonhuman primates, MPTP can produce a parkinsonian syndrome that replicates almost all of the features of
PD, including bradykinesia, rigidity, and postural abnormalities. The resting tremor and the lewy body inclusion, are
however hardly encountered in the MPTP-treated monkey.
It would seem, however, that, rather than a question of strain,
it is a question of schedule of MPTP administration. Indeed,
old paradigms used high doses of MPTP administration to
produce acute and severe DA loss, which failed to reproduce
the progressive nature of PD. At present, long-term administration of low doses of MPTP seems to be a more accurate
approach to mimic the human PD pathogenesis with a slow
evolution of parkinsonian syndrome. This model has also
been valuable for the study of dyskinesia, since regular use of
levodopa or DA agonists induces these incapacitating side
effects in the MPTP-treated monkey as it does in humans.
While nonmotor symptoms of PD were more and
more acknowledged as debilitating and critical unmet
needs for PD patients, the MPTP monkey model(s) has
been further studied for establishing if they were present
as well. In fact, to our surprise, the MPTP monkey model
recapitulates most if not all the motor and nonmotor
symptoms. Cognitive impairments have been the first to
be acknowledged and a specific model, the so-called
chronic low dose model has even been specifically developed to this aim. Interestingly, levodopa impairs cognitive
capabilities in these MPTP monkeys while motor symptoms are improved, exactly as in PD patients. Accordingly,
the sleep disturbances, excessive daytime sleepiness and
rapid eye moment (REM) sleep deregulation that are
among the most frequent and disabling nonmotor manifestations in PD are fully reproduced in MPTP monkeys
offering the possibility to now investigate the pathophysiology of these disorders and to test putative therapeutics.
Currently, MPTP neurotoxicity is the best available
animal model to evaluate the efficacy of neuroprotective
and neurorestorative strategies of PD. Like the 6-OHDA
model, the MPTP model has facilitated enormously the
comprehension of the pathophysiology of the basal ganglia but also opened up new areas of research including
drugs, transplants, and gene therapy. Observation of nonmotor symptoms in MPTP monkeys has also opened a
new field of research and offers a platform for validating
therapeutics aiming at controlling these symptoms.
Environmental Toxins Models
Several epidemiological and toxicological studies have
suggested that pesticides and other environmental toxins
could be involved in the pathogenesis of PD. Among the
environmental toxin models of PD, paraquat, maneb
(manganese ethylenebisdithiocarbamate), and rotenone
have received the largest attention. One potential mechanism by which all these toxins may increase the risk for
PD is through disruption of mitochondrial function.
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In rodents, paraquat leads to SNpc DA neuron degeneration accompanied by a-synuclein containing inclusions.
Combined with maneb, the effects on the loss of DA
neurons and on reduced motor activity are greater than
with paraquat alone. Nevertheless these studies are marginal and failed to provide conclusive evidence to consider
pesticide model as reliable experimental model of PD.
Rotenone-infused rats resulted in a progressive formation of cytoplasmic inclusions and loss of nigral DA neurons leading to motor behavioral impairment. These
motor abnormalities were reversed by levodopa. Although
this model produced most of key features of PD, it originally suffered from much variability since some animals
had lesions and others not. Further, rotenone induced a
chronically progressive degeneration of DA neurons and
also of non-DA neurons in both the basal ganglia and the
brainstem. This model is thus more a multisystemic
model of degeneration than originally proposed on DA
neurons selectively. However, recent refinement of both
the administration and the procedures have allowed to
solve some of these issues, making rotenone appealing
again especially considering it is multisystemic and its
capacity to produce cytoplasmic inclusions.
Similarly to rotenone, chronic administration of annonacin, another inhibitor of complex I of the mitochondrial
respiratory chain cause nigral and striatal (non-DAergic)
neurodegeneration. Finally, proteasome inhibitors have
been suggested as potential PD inducers. Several expert
laboratories despite huge efforts did, however, not replicate this model.
Gene-Based Models
The discovery of several genetic alterations in familial forms
of PD has enabled the development of a gene-based
approach to create animal models. Genes involved in familial PD include a-synuclein, parkin, UCH-L1, PINK1, DJ-1,
and LRKK2. The development of models of PD based on
genes implicated in familial form has been carried out using
either transgenesis or viral-mediated expression.
Transgenic Models
a-synuclein being the pathological hallmark of sporadic
PD, it has been the focus of most endeavours to create a
genetic model of the disease. In addition, the discovery of
genomic multiplication of a-synuclein in some families
demonstrated the pathogenicity of increased levels of the
wild-type protein. Numerous lines expressing wild-type
or mutated human a-synuclein have been generated.
Most lines recapitulate the propensity of some neuronal
populations to host protein aggregates (olfactory bulb,
midbrain, cortex, etc.) as found in the human disease.
Some lines also display nigrostriatal alterations as shown
by a reduction of tyrosine hydroxylase (TH) positive
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Parkinson’s Disease: Animal Models
fibers in the striatum or progressive DA cell loss in the
SNc. In one line, overexpression of truncated a-synuclein
results in a loss of DA neurons in the SNc and a concomitant reduction of DA levels in the striatum. Several reasons may account for the lack of systematic DA
neurodegeneration, including expression levels within
the SNc, coexistence of human and mouse a-synuclein,
upregulation of cellular defense mechanisms in response
to constitutive over expression of the protein.
Among parkin knock-out models, two lines (exon 3 or
7 deletion) display alteration of DA release or metabolism
and one of these lines also exhibit a loss of TH neurons in
the locus coeruleus.
Two lines of DJ-1 mutant mice have been generated,
with either targeted deletion of DJ-1 exon 2 or a stop
codon inserted in exon 1. Both strategies failed to induce
DA degeneration. However, one line showed an increased
vulnerability to MPTP which could be reversed by viralmediated expression of wild-type DJ-1.
Spontaneous in-frame deletion of UCH-L1 exons
7 and 8 leads to gracile axonal dystrophy (gad) in mice.
These gad mice display tremor and ataxia due to axonal
degeneration of motor and sensory neurons together with
the accumulation of b-amyloid and ubiquitinated proteins. Expression of human mutant UCH-L1 (I93M) on
a gad background led to a moderate loss of DA neurons in
the SNc and DA in the striatum.
The justified disappointment in view of the lack of
robust DA neurodegeneration in most transgenic models
should be tempered by the fact that these models offer the
opportunity to study molecular interactions between
genes and pathways involved in the pathophysiology of
PD. Also, understanding how mice can cope with genetic
alterations that cause PD in humans will be a unique
chance to explore future neuroprotective strategies.
Viral-Based Models
Viral-mediated expression of human a-synuclein (WT or
A53T) has been shown to induce the formation of cytoplasmic inclusion, neuritic pathology and neurodegeneration in
both rats and primates. Interestingly, this approach has been
used to demonstrate the neuroprotective role of parkin in
a-synuclein-induced DA degeneration. Thus viral-based
models appear suitable to study the molecular mechanisms
of a-synuclein-induced DA neurodegeneration and to test
neuroprotective strategies but would now require much
more attention that they have so far.
Conclusion
Currently available animal models of PD have lead
largely to a better understanding of PD pathophysiology
and pathogenesis as well as provide clues to novel targets
for to the development of new or improved neuroprotective drugs. With regard to the development of symptomatic treatments, the MPTP primate models appear as
mimicking more and more closely the human condition
and represent therefore the gold standard for validating
any symptomatic strategy. However, none of the currently
available models reproduce the progressive loss of DA
neuron that is characteristic of human PD. PD is a chronic
and progressive disease whereas the numerous animal
models at our disposal are produced either by acute lesion
or by semichronic intoxication and thus, only offer stable
models of nigral lesion. Transgenic models allow addressing complementary aspects of PD and will be important
in understanding the aetiology and progression of PD.
Although no perfect animal model of PD exists yet, future
models could include a combination of both neurotoxin
and genetically induced changes considering that both
environmental and genetic factors are involved in the
pathogenesis of PD. The benefit of this research will
not be limited to PD. A clearer understanding of the
dynamic process of neurodegeneration – the impact of
the death of certain neurones on the entire neuronal
system – will shed light on the whole field of neurodegenerative pathologies.
See also: 6-OH Dopamine Rat Model; Complex I Deficiency;
Dopamine Depletors and Movement Disorders; Dyskinesias; MPTP; Neurofibrillary Tangles; Neuroleptics and
Movement Disorders; PARK1, Alpha Synuclein; Parkinson’s
Disease: Definition, Diagnosis, and Management; Parkinson’s Disease: Genetics; Pesticides; Stereology.
Further Reading
Betarbet R, Sherer TB, and Greenamyre JT (2002) Animal models of
Parkinson’s disease. Bioessays 24: 308–318.
Bezard E, Imbert C, and Gross CE (1998) Experimental models of
Parkinson’s disease: From the static to the dynamic. Reviews in the
Neurosciences 9: 71–90.
Cenci MA, Whishaw IQ, and Schallert T (2002) Animal models of
neurological deficits: How relevant is the rat? Nature Reviews
Neuroscience 3: 574–579.
Dauer W and Przedborski S (2003) Parkinson’s disease: Mechanisms
and models. Neuron 39: 889–909.
Di Monte DA (2003) The environment and Parkinson’s disease: Is the
nigrostriatal system preferentially targeted by neurotoxins? Lancet
Neurology 2: 531–538.
Fernagut PO and Chesselet MF (2004) Alpha-synuclein and transgenic
mouse models. Neurobiology of Disease 17: 123–130.
Schneider JS and Roeltgen DP (1993) Delayed matching-to-sample,
object retrieval, and discrimination reversal deficits in chronic low
dose MPTP-treated monkeys. Brain Research 615: 351–354.
Schwarting RK and Huston JP (1996) The unilateral 6-hydroxydopamine
lesion model in behavioral brain research. Analysis of functional deficits,
recovery and treatments. Progress in Neurobiology 50: 275–331.
Simola N, Morelli M, and Carta AR (2007) The 6-hydroxydopamine
model of Parkinson’s disease. Neurotoxicity Research 11: 151–167.
Ulusoy A, Bjorklund T, Hermening S, and Kirik D (2008) In vivo gene
delivery for development of mammalian models for Parkinson’s
disease. Experimental Neurology 209: 89–100.
Encyclopedia of Movement Disorders (2010), vol. 3, pp. 420-424
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