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Parkinson's disease: animal models

2007, Handbook of Clinical Neurology

) commercial reprints, selling or licensing of copies or access, or posting on open internet sites, personal or institution websites or repositories, are prohibited. For exception, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial 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.

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/235428265 Parkinson’s Disease: Animal Models Chapter · February 2010 DOI: 10.1016/B978-0-12-374105-9.00221-5 CITATIONS READS 0 52 3 authors: Grégory Porras Pierre-Olivier Fernagut 38 PUBLICATIONS 1,148 CITATIONS 75 PUBLICATIONS 2,423 CITATIONS University of Bordeaux SEE PROFILE Université Victor Segalen Bordeaux 2 SEE PROFILE Erwan Bezard University of Bordeaux 312 PUBLICATIONS 11,029 CITATIONS SEE PROFILE All content following this page was uploaded by Grégory Porras on 20 January 2017. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately. This article was originally published in Encyclopedia of Movement Disorders, published by Elsevier. The attached copy is provided by Elsevier for the author’s benefit and for the benefit of the author’s institution. It may be used for non-commercial research and educational use, including (without limitation) use in instruction at your institution, distribution to specific colleagues who you know, and providing a copy to your institution’s administrator. All other uses, reproduction and distribution, including (without limitation) commercial reprints, selling or licensing of copies or access, or posting on open internet sites, personal or institution websites or repositories, are prohibited. For exception, permission may be sought for such use through Elsevier’s permissions site at: http://www.elsevier.com/locate/permissionusematerial 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 Encyclopedia of Movement Disorders (2010), vol. 3, pp. 420-424 Author's personal copy 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. 421 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), Encyclopedia of Movement Disorders (2010), vol. 3, pp. 420-424 Author's personal copy 422 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. Encyclopedia of Movement Disorders (2010), vol. 3, pp. 420-424 Author's personal copy 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. 423 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 Encyclopedia of Movement Disorders (2010), vol. 3, pp. 420-424 Author's personal copy 424 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 View publication stats