The application of Russell and Burch 3R principle in rodent models of neurodegenerative disease: The case of Parkinson’s disease

Currently, the accepted ethical standards for the regulation of animal experimentation are provided by the 3R principle (Replacement, Reduction and Refinement). The development of alternative methods to the use of animals (Replacement), the design of adequate experimental protocols to reduce the number of animals (Reduction), the application of refinement practices (Refinement) are all aspects to be considered to ensure ethical and scientific validity to animal experimentation. This review intends to address these issues, using experimental research on Parkinson's disease (PD) as a paradigmatic example of the use of animal models to improve knowledge on a devastating human pathology. In particular, current rodent models of PD and their validity are reviewed and discussed, and methodologies that may ultimately reduce animal's suffering emphasized. Although procedures referring to with 3R principle can be traced in the literature reviewed, they are not considered yet an important part of the methodological information. The formal inclusion in scientific papers of a section devoted to 3Rs may increase knowledge and eventually adherence to this principle by scientists.

[1]  A. Blackburn,et al.  Parkinson's disease, pesticides, and glutathione transferase polymorphisms , 1998, The Lancet.

[2]  Sanford P. Markey,et al.  Chronic parkinsonism secondary to intravenous injection of meperidine analogues , 1979, Psychiatry Research.

[3]  Suzanne Imbriglio Environmental Enrichment Slows Disease Progression in R6/2 Huntingtonʼs Disease Mice. , 2002 .

[4]  C. Gerfen,et al.  D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. , 1990, Science.

[5]  B. Spruijt,et al.  Access to enriched housing is rewarding to rats as reflected by their anticipatory behaviour , 2003, Animal Behaviour.

[6]  W. Bender,et al.  A Drosophila model of Parkinson's disease , 2000, Nature.

[7]  T. Di Paolo,et al.  Stereospecific prevention by 17β‐estradiol of MPTP‐induced dopamine depletion in mice , 2000, Synapse.

[8]  J. O'Callaghan,et al.  The impact of gender and estrogen on striatal dopaminergic neurotoxicity. , 1998, Annals of the New York Academy of Sciences.

[9]  B. Spruijt,et al.  Isolation changes the incentive value of sucrose and social behaviour in juvenile and adult rats , 1999, Behavioural Brain Research.

[10]  B. Szekely,et al.  Adjunctive treatment in Parkinson's disease: physical therapy and comprehensive group therapy. , 1982, Rehabilitation literature.

[11]  Jacob Cohen Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[12]  Michael J. Campbell,et al.  Statistical tables for the design of clinical trials , 1987 .

[13]  G. Barrie Wetherill,et al.  Sequential methods in statistics , 1967 .

[14]  V. Russell,et al.  Voluntary Running Provides Neuroprotection in Rats After 6-Hydroxydopamine Injection into the Medial Forebrain Bundle , 2004, Metabolic Brain Disease.

[15]  S. Lewis,et al.  Cognitive Deficits and Psychosis in Parkinson’s Disease , 2006, CNS drugs.

[16]  A. Tamas,et al.  Age and gender differences in behavioral and morphological outcome after 6-hydroxydopamine-induced lesion of the substantia nigra in rats , 2005, Behavioural Brain Research.

[17]  E. Masliah,et al.  alpha-synuclein promotes mitochondrial deficit and oxidative stress. , 2000, The American journal of pathology.

[18]  Saber M Hussain,et al.  The interaction of manganese nanoparticles with PC-12 cells induces dopamine depletion. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[19]  U. Ungerstedt Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. , 1971, Acta physiologica Scandinavica. Supplementum.

[20]  A. Carlsson,et al.  3,4-Dihydroxyphenylalanine and 5-Hydroxytryptophan as Reserpine Antagonists , 1957, Nature.

[21]  S. Thobois,et al.  Génétique et facteurs environnementaux de la maladie de Parkinson , 2002 .

[22]  J. Trojanowski,et al.  Transgenic Models of Tauopathies and Synucleinopathies , 1999, Brain pathology.

[23]  Joseph P Huston,et al.  Behavioral phenotyping of the MPTP mouse model of Parkinson's disease , 2001, Behavioural Brain Research.

[24]  A. Barnekow,et al.  Effects of different forms of environmental enrichment on behavioral, endocrinological, and immunological parameters in male mice , 2003, Hormones and Behavior.

[25]  V. Baumans,et al.  Strain specific behavioural response to environmental enrichment in the mouse. , 1994, Journal of experimental animal science.

[26]  Linda MacDonald Glenn When pigs fly? Legal and ethical issues in transgenics and the creation of chimeras. The Walter C. Randall Biomedical Ethics Lecture. , 2003, The Physiologist.

[27]  H. W. Schultz Animal Welfare Act , 1981 .

[28]  I. Date,et al.  Long-term effect of MPTP in the mouse brain in relation to aging: neurochemical and immunocytochemical analysis , 1990, Brain Research.

[29]  Augusto Vitale,et al.  The 3R principle and the use of non-human primates in the study of neurodegenerative diseases: The case of Parkinson's disease , 2009, Neuroscience & Biobehavioral Reviews.

[30]  W. Dauer,et al.  Parkinson's Disease Mechanisms and Models , 2003, Neuron.

[31]  E. Masliah,et al.  α-Synuclein Promotes Mitochondrial Deficit and Oxidative Stress , 2000 .

[32]  F. Gage,et al.  Fibroblast growth factor-2-producing fibroblasts protect the nigrostriatal dopaminergic system from 6-hydroxydopamine , 2000, Brain Research.

[33]  Marten P. Smidt,et al.  Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice , 2006, Proceedings of the National Academy of Sciences.

[34]  M. Youdim,et al.  M30, a novel multifunctional neuroprotective drug with potent iron chelating and brain selective monoamine oxidase-ab inhibitory activity for Parkinson's disease. , 2006, Journal of neural transmission. Supplementum.

[35]  Anticipation of play elicits high-frequency ultrasonic vocalizations in young rats. , 1998 .

[36]  Todd B. Sherer,et al.  Chronic systemic pesticide exposure reproduces features of Parkinson's disease , 2000, Nature Neuroscience.

[37]  T. Dawson Parkin and defective ubiquitination in Parkinson's disease. , 2006, Journal of neural transmission. Supplementum.

[38]  R. Behringer,et al.  Manipulating the Mouse Embryo: A Laboratory Manual , 2002 .

[39]  J. Engele,et al.  The neurotrophic effects of fibroblast growth factors on dopaminergic neurons in vitro are mediated by mesencephalic glia [published erratum appears in J Neurosci 1992 Mar;12(3):685] , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[40]  MoonHee Lee,et al.  Effect of the overexpression of wild‐type or mutant α‐synuclein on cell susceptibility to insult , 2001 .

[41]  G. Petzinger,et al.  The parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP): a technical review of its utility and safety , 2001, Journal of neurochemistry.

[42]  R. McKay,et al.  A Specific Survival Response in Dopamine Neurons at Most Risk in Parkinson's Disease , 2006, The Journal of Neuroscience.

[43]  M. Zigmond,et al.  Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine , 2001, The Journal of Neuroscience.

[44]  Alena Savonenko,et al.  Transgenic mouse models of neurodegenerative disease: Opportunities for therapeutic development , 2002, Current neurology and neuroscience reports.

[45]  Makoto Hashimoto,et al.  Transgenic Models of α‐Synuclein Pathology , 2003 .

[46]  T. Sherer,et al.  Mechanistic Approaches to Parkinson's Disease Pathogenesis , 2002, Brain pathology.

[47]  H. Würbel Publications should include an animal-welfare section , 2007, Nature.

[48]  Dwaine F Emerich,et al.  Rats with partial striatal dopamine depletions exhibit robust and long-lasting behavioral deficits in a simple fixed-ratio bar-pressing task , 1997, Behavioural Brain Research.

[49]  David C. Dorman,et al.  Manganese Dosimetry: Species Differences and Implications for Neurotoxicity , 2005, Critical reviews in toxicology.

[50]  G. Bignami From entropy to Duino , 1999, Nature.

[51]  V. Baumans,et al.  Do Male Mice Prefer or Avoid Each Other's Company? Influence of Hierarchy, Kinship, and Familiarity , 2001 .

[52]  K. Takata,et al.  Inhibitory effects of antiparkinsonian drugs and caspase inhibitors in a parkinsonian flatworm model. , 2003, Journal of pharmacological sciences.

[53]  J. Trojanowski,et al.  Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. , 2002, Science.

[54]  G. Yancopoulos,et al.  BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra , 1991, Nature.

[55]  K. Unsicker,et al.  Glial Cell Line-Derived Neurotrophic Factor Requires Transforming Growth Factor-β for Exerting Its Full Neurotrophic Potential on Peripheral and CNS Neurons , 1998, The Journal of Neuroscience.

[56]  P. Brain,et al.  Refining rodent husbandry: the mouse: Report of the Rodent Refinement Working Party , 1998, Laboratory animals.

[57]  M. Youdim,et al.  Novel multifunctional neuroprotective iron chelator‐monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition , 2005, Journal of neurochemistry.

[58]  K. S. Bankiewicz,et al.  A 6-hydroxydopamine-induced selective parkinsonian rat model , 1989, Brain Research.

[59]  Satoru Kobayashi,et al.  Effects of enriched environments with different durations and starting times on learning capacity during aging in rats assessed by a refined procedure of the Hebb‐Williams maze task , 2002, Journal of neuroscience research.

[60]  C. Sherwin,et al.  Housing conditions affect self-administration of anxiolytic by laboratory mice , 2004, Animal Welfare.

[61]  J. Salamone,et al.  Involvement of ventrolateral striatal dopamine in movement initiation and execution: A microdialysis and behavioral investigation , 1996, Neuroscience.

[62]  Jos Prickaerts,et al.  Modeling Parkinson's Disease in Rats: An Evaluation of 6-OHDA Lesions of the Nigrostriatal Pathway , 2002, Experimental Neurology.

[63]  J. B. Justice,et al.  Dopamine depletion in a striatal subregion disrupts performance of a skilled motor task in the rat , 1985, Brain Research.

[64]  M. Hoane,et al.  Incomplete nigrostriatal dopaminergic cell loss and partial reductions in striatal dopamine produce akinesia, rigidity, tremor and cognitive deficits in middle-aged rats , 1999, Behavioural Brain Research.

[65]  Qin Li,et al.  The 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitor Lovastatin Reduces Severity of l-DOPA-Induced Abnormal Involuntary Movements in Experimental Parkinson's Disease , 2008, The Journal of Neuroscience.

[66]  Y. Kitamura,et al.  Neuroprotective Mechanisms of Antiparkinsonian Dopamine D2-Receptor Subfamily Agonists , 2003, Neurochemical Research.

[67]  R. Richardson,et al.  Effects of Environmental Enrichment on Rate of Contextual Processing and Discriminative Ability in Adult Rats , 2000, Neurobiology of Learning and Memory.

[68]  C. J. Moore,et al.  Transgenesis and Animal Welfare , 1995, Alternatives to laboratory animals : ATLA.

[69]  B. Halliwell,et al.  Effect of the overexpression of wild-type or mutant alpha-synuclein on cell susceptibility to insult. , 2001, Journal of neurochemistry.

[70]  Patrick Bateson,et al.  When to experiment on animals. , 1986, New scientist.

[71]  W. Russell,et al.  Ethical and Scientific Considerations Regarding Animal Testing and Research , 2011, PloS one.

[72]  Mark R. Rosenzweig,et al.  Enriched and impoverished environments , 1987 .

[73]  D. Dluzen,et al.  Estrogen as a neuroprotectant against MPTP-induced neurotoxicity in C57/B1 mice. , 1996, Neurotoxicology and teratology.

[74]  B. Costall,et al.  Neurotoxic Sesquiterpenoids from the Yellow Star Thistle Centaurea solstitialis L. (Asteraceae) , 1991 .

[75]  I. Olsson,et al.  Improving housing conditions for laboratory mice: a review of 'environmental enrichment' , 2002, Laboratory animals.

[76]  P. Brain,et al.  Re®ning rodent husbandry: the mouse , 1998 .

[77]  J. Balcombe,et al.  Laboratory environments and rodents' behavioural needs: a review , 2006, Laboratory animals.

[78]  P. Barnéoud,et al.  Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat , 1995, Neuroscience.

[79]  L. Tremblay,et al.  Experimental Models of Parkinson’s Disease , 2002, Annales pharmaceutiques francaises.

[80]  G. Calamandrei Ethological and methodological considerations in the use of newborn rodents in biomedical research. , 2004, Annali dell'Istituto superiore di sanita.

[81]  C. C. Johnson,et al.  The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living , 1998, Neurology.

[82]  Anders Björklund,et al.  Prospects for new restorative and neuroprotective treatments in Parkinson's disease , 1999, Nature.

[83]  M. Chesselet,et al.  Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. , 2004, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[84]  K. Murray,et al.  Phenotyping of genetically engineered mice: humane, ethical, environmental, and husbandry issues. , 2006, ILAR journal.

[85]  E. J. Green,et al.  Therapeutic Effects of Environmental Enrichment on Cognitive Function and Tissue Integrity Following Severe Traumatic Brain Injury in Rats , 2001, Experimental Neurology.

[86]  T. Voss,et al.  Effects of environmental enrichment on aggressive behavior, dominance hierarchies, and endocrine states in male DBA/2J mice , 1994, Physiology & Behavior.

[87]  D. Harper,et al.  Journal of Applied Animal Welfare Science Behavioral Indexes of Poor Welfare in Laboratory Rats , 2022 .

[88]  A. M. Snyder,et al.  Stress‐induced neurological impairments in an animal model of parkinsonism , 1985, Annals of neurology.

[89]  Patrick Bateson,et al.  Assessment of pain in animals , 1991, Animal Behaviour.

[90]  John Q. Trojanowski,et al.  Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease , 2001, Science.

[91]  C. Barnard,et al.  Housing and welfare in laboratory rats: time-budgeting and pathophysiology in single-sex groups , 1996, Animal Behaviour.

[92]  G. Koob,et al.  Extended Access to Nicotine Self-Administration Leads to Dependence: Circadian Measures, Withdrawal Measures, and Extinction Behavior in Rats , 2007, Journal of Pharmacology and Experimental Therapeutics.

[93]  T. Sherer,et al.  Animal models of Parkinson's disease. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[94]  Jonathan Salcedo,et al.  Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human α-Synuclein , 2004, The Journal of Neuroscience.

[95]  L. V. Zutphen,et al.  Nesting Material as Environmental Enrichment Has No Adverse Effects on Behavior and Physiology of Laboratory Mice , 1997, Physiology & Behavior.

[96]  F. Archibald,et al.  Manganese poisoning and the attack of trivalent manganese upon catecholamines. , 1987, Archives of biochemistry and biophysics.

[97]  A. Still,et al.  On the number of subjects used in animal behaviour experiments , 1982, Animal Behaviour.

[98]  A. Björklund,et al.  l-DOPA-Induced Dyskinesia in the Intrastriatal 6-Hydroxydopamine Model of Parkinson's Disease: Relation to Motor and Cellular Parameters of Nigrostriatal Function , 2002, Neurobiology of Disease.

[99]  T. Robbins,et al.  Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention , 1985, Nature.

[100]  H. Würbel Ideal homes? Housing effects on rodent brain and behaviour , 2001, Trends in Neurosciences.

[101]  I. Whishaw,et al.  Disruption of central cholinergic systems in the rat by basal forebrain lesions or atropine: Effects on feeding, sensorimotor behaviour, locomotor activity and spatial navigation , 1985, Behavioural Brain Research.

[102]  T. Wolfle Introduction: environmental enrichment. , 2005, ILAR journal.

[103]  J. Talling,et al.  Familiarity increases consistency in animal tests , 2005, Behavioural Brain Research.

[104]  J. Langston,et al.  Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. , 1983, Science.

[105]  Thomas Hartung,et al.  Workgroup Report: Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity into International Hazard and Risk Assessment Strategies , 2007, Environmental health perspectives.

[106]  Y. Agid,et al.  Dopaminergic sprouting in the rat striatum after partial lesion of the substantia nigra , 1996, Brain Research.

[107]  Brian Knutson,et al.  Anticipation of play elicits high-frequency ultrasonic vocalizations in young rats. , 1998, Journal of comparative psychology.

[108]  M. Chesselet,et al.  Alpha-synuclein and transgenic mouse models , 2004, Neurobiology of Disease.

[109]  S. Vandewoude,et al.  Species-specific assessment of pain in laboratory animals. , 2003, Contemporary topics in laboratory animal science.

[110]  Hua-qing Liu,et al.  A delivery strategy for rotenone microspheres in an animal model of Parkinson's disease. , 2006, Biomaterials.

[111]  A. Hannan,et al.  Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders , 2008, Neurobiology of Disease.

[112]  Makoto Hashimoto,et al.  Transgenic models of alpha-synuclein pathology: past, present, and future. , 2003, Annals of the New York Academy of Sciences.

[113]  K. Unsicker,et al.  Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[114]  C. Sortwell,et al.  Diminished Survival of Mesencephalic Dopamine Neurons Grafted into Aged Hosts Occurs during the Immediate Postgrafting Interval , 2001, Experimental Neurology.

[115]  Gerd Kempermann,et al.  Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. , 2003, Cerebral cortex.

[116]  C. Barnard,et al.  Housing and welfare in laboratory rats: effects of cage stocking density and behavioural predictors of welfare , 1999, Animal Behaviour.

[117]  Roger M. Nitsch,et al.  Laboratory animal welfare: Cage enrichment and mouse behaviour , 2004, Nature.

[118]  H. Buchanan-Smith,et al.  Harmonising the definition of refinement , 2005, Animal Welfare.

[119]  M. Chesselet,et al.  Genetic mouse models of parkinsonism: Strengths and limitations , 2005, NeuroRX.

[120]  R. Morris Spatial Localization Does Not Require the Presence of Local Cues , 1981 .

[121]  G. Wooten,et al.  Are men at greater risk for Parkinson’s disease than women? , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[122]  L. Hurley The roles of trace elements in foetal and neonatal development. , 1981, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[123]  S Shimohama,et al.  The parkinsonian models: invertebrates to mammals. , 2000, Japanese journal of pharmacology.

[124]  A. Björklund,et al.  Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat , 1996, Neuroscience.

[125]  M. Yang,et al.  Environmental enrichment: effects on stereotyped behavior and regional neuronal metabolic activity , 2002, Brain Research.

[126]  T. Azar,et al.  Stress-like responses to common procedures in male rats housed alone or with other rats. , 2002, Contemporary topics in laboratory animal science.

[127]  Mepham Tb,et al.  Transgenesis and animal welfare. , 1995 .

[128]  E. Masliah,et al.  Transgenic animal models of neurodegenerative diseases and their application to treatment development. , 2007, Advanced drug delivery reviews.

[129]  Anders Björklund,et al.  Characterization of Behavioral and Neurodegenerative Changes Following Partial Lesions of the Nigrostriatal Dopamine System Induced by Intrastriatal 6-Hydroxydopamine in the Rat , 1998, Experimental Neurology.

[130]  Bengt Winblad,et al.  Dopaminergic Deficiency is More Pronounced in Putamen than in Nucleus Caudatus in Parkinson's Disease , 1983 .

[131]  G. B. Wetherill,et al.  Sequential Methods in Statistics. , 1972 .

[132]  P. Townsend Use of in-cage shelters by laboratory rats , 1997 .

[133]  G. Jackson,et al.  Drosophila models of neurodegenerative disease , 2005, NeuroRX.

[134]  T. Schallert,et al.  Reactive capacity: A sensitive behavioral marker of movement initiation and nigrostriatal dopamine function , 1985, Brain Research.

[135]  J. Panksepp,et al.  Tickling induces reward in adolescent rats , 2001, Physiology & Behavior.

[136]  Y. Mitsumoto,et al.  Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice , 2006, Neuroscience Letters.

[137]  L. Ricceri,et al.  Refining learning and memory assessment in laboratory rodents. An ethological perspective. , 2004, Annali dell'Istituto superiore di sanita.

[138]  C. Stichel,et al.  The mouse MPTP model: gene expression changes in dopaminergic neurons , 2003, The European journal of neuroscience.

[139]  B. Davidson,et al.  Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat , 1999, Gene Therapy.

[140]  R. Schwarz,et al.  Patterns of psychological problems in Parkinson's disease , 2005, Acta neurologica Scandinavica.

[141]  W. Langhans,et al.  Enrichment-dependent differences in novelty exploration in rats can be explained by habituation , 2001, Behavioural Brain Research.

[142]  Penny Hawkins,et al.  Recognizing and assessing pain, suffering and distress in laboratory animals: a survey of current practice in the UK with recommendations , 2002, Laboratory animals.

[143]  L. Stehno-Bittel,et al.  Endurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of Parkinsonism with severe neurodegeneration , 2007, Neuroscience.

[144]  T. Schallert,et al.  An intermittent, controlled-rate, slow progressive degeneration model of Parkinson’s disease: antiparkinson effects of Sinemet and protective effects of methylphenidate , 2005, Behavioural Brain Research.

[145]  J. W. Rudy,et al.  Brief exposure to an enriched environment improves performance on the Morris water task and increases hippocampal cytosolic protein kinase C activity in young rats , 1992, Behavioural Brain Research.

[146]  David G. Porter,et al.  Ethical scores for animal experiments , 1992, Nature.

[147]  P. H. Griffiths,et al.  Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment , 1985, Veterinary Record.

[148]  G. Miller,et al.  Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease , 2003, Neuroscience.

[149]  Douglas G Altman,et al.  Guidelines for the design and statistical analysis of experiments using laboratory animals. , 2002, ILAR journal.

[150]  A. Björklund,et al.  Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[151]  E. Alleva,et al.  Problems of test choice and data analysis in behavioral teratology: the case of prenatal benzodiazepines. , 1987, Neurotoxicology and teratology.

[152]  P. Riederer,et al.  Animal models of Parkinson's disease: An empirical comparison with the phenomenology of the disease in man , 2005, Journal of Neural Transmission.

[153]  J. Cummings,et al.  Depression and Parkinson's disease: a review. , 1992, The American journal of psychiatry.

[154]  S. Dunnett,et al.  Differential effects of unilateral striatal and nigrostriatal lesions on grip strength, skilled paw reaching and drug-induced rotation in the rat , 2001, Brain Research Bulletin.

[155]  M Puopolo,et al.  Behavioural effects of endocrine disrupting chemicals on laboratory rodents: statistical methodologies and an application concerning developmental PCB exposure. , 1999, Chemosphere.

[156]  S. Wachtel,et al.  Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson's disease: studies on medial forebrain bundle and striatal lesions , 1999, Neuroscience.

[157]  D. Broom,et al.  Investigations into the preferences of laboratory rats for nest-boxes and nesting materials , 1998, Laboratory animals.

[158]  T. Humby,et al.  Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease , 2006, The European journal of neuroscience.

[159]  S. Markey,et al.  MPTP toxicity: implications for research in Parkinson's disease. , 1988, Annual review of neuroscience.

[160]  Todd B. Sherer,et al.  Mechanism of Toxicity in Rotenone Models of Parkinson's Disease , 2003, The Journal of Neuroscience.

[161]  Elissa J. Chesler,et al.  Influences of laboratory environment on behavior , 2002, Nature Neuroscience.

[162]  T. Sherer,et al.  Pathogenesis of Parkinson's disease. , 2001, Current opinion in investigational drugs.

[163]  S. Kish,et al.  Brain neurotransmitters in dystonia musculorum deformans. , 1986, The New England journal of medicine.

[164]  J. Langston,et al.  Permanent human parkinsonism due to 1‐methy 1–4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) , 1985, Neurology.

[165]  H. Teräväinen,et al.  Animal models of parkinsonism. , 1990, Pharmacology & toxicology.

[166]  T. Poole,et al.  Happy animals make good science , 1997, Laboratory animals.

[167]  M. Emborg Evaluation of animal models of Parkinson's disease for neuroprotective strategies , 2004, Journal of Neuroscience Methods.

[168]  P. Jenner,et al.  The contribution of the MPTP-treated primate model to the development of new treatment strategies for Parkinson's disease. , 2003, Parkinsonism & related disorders.

[169]  V. Russell,et al.  Stress reduces the neuroprotective effect of exercise in a rat model for Parkinson's disease , 2005, Behavioural Brain Research.

[170]  C. Markham,et al.  Neurotoxic effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the cat. Tyrosine hydroxylase immunohistochemistry , 1986, Brain Research.

[171]  S. Speciale,et al.  MPTP: insights into parkinsonian neurodegeneration. , 2002, Neurotoxicology and teratology.

[172]  M. Chesselet,et al.  Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype α-synuclein , 2006, Neuroscience.

[173]  T. Oury,et al.  Manganese Superoxide Dismutase Protects against 6-Hydroxydopamine Injury in Mouse Brains* , 2005, Journal of Biological Chemistry.

[174]  E. Hirsch Nigrostriatal system plasticity in Parkinson's disease: effect of dopaminergic denervation and treatment. , 2000, Annals of neurology.

[175]  C. Sortwell,et al.  Diminished Viability, Growth, and Behavioral Efficacy of Fetal Dopamine Neuron Grafts in Aging Rats with Long-Term Dopamine Depletion: An Argument for Neurotrophic Supplementation , 1999, The Journal of Neuroscience.

[176]  E. Patterson-Kane Cage Size Preference in Rats in the Laboratory , 2002, Journal of applied animal welfare science : JAAWS.