Journal of Neuroimmune Pharmacology

, Volume 7, Issue 1, pp 279–288 | Cite as

Murine Motor and Behavior Functional Evaluations for Acute 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) Intoxication

  • Jessica A. L. Hutter-Saunders
  • Howard E. GendelmanEmail author
  • R. Lee Mosley


Acute intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal neurodegeneration that reflects Parkinson’s disease (PD) pathobiology. The model is commonly used for rodent studies of PD pathogenesis and diagnostics and for developmental therapeutics. However, tests of motor function in MPTP-intoxicated mice have yielded mixed results. This unmet need reflects, in part, lesion severity, animal variability, and the overall test sensitivity and specificity. In attempts to standardize rodent motor function and behavioral tests, mice were trained on the rotarod or habituated in an open field test chamber, and baseline performance measurements were collected prior to MPTP intoxication. One week following MPTP intoxication, motor function and behavior were assessed and baseline measurements applied to post-MPTP measurements with normalization to PBS controls. Rotarod and open field tests assessed in this manner demonstrated significant differences between MPTP- and saline-treated mice, while tests of neuromuscular strength and endurance did not. We conclude that the rotarod and open field tests provide reliable measures of motor function for MPTP-intoxicated mice.


Parkinson’s disease MPTP Behavior Mice Rotarod Open field Grooming 



We would like to thank Megan Willer and Alex Braun for help with data collection; Rebecca Banerjee, Adelina Holguin, and Kalipada Pahan for advice on experimental methods and design; and Stephen Bonasera for discussions that enhanced the depth of this work. This work is supported by NIH grants 2R01 NS034239, P20 RR15635, P30 AI42845, P01 DA028555, P20 RR15635, and 5R01 NS36126, 1R01 NS070190, 1 P01 NS043985-01, P01 MH64570, 1R01 MH083516, P20 DA026146, and PO1 NS31492.


The authors have no financial conflict of interest.

Supplementary material

11481_2011_9269_Fig5_ESM.gif (27 kb)
Supplemental Fig. 1

MPTP-induced affect on stride length. Mice were treated with PBS or four injections of MPTP at 18, 20, 22, and 24 mg/kg/injection. One week after treatment, the stride lengths of mice were measured using the ink paw print test on a white papered gangway leading into the home cage. Mean stride lengths were determined for four to six mice/group and significant differences among means were determined by one-way ANOVA and pair-wise comparisons determined by Tukey’s HSD post hoc analysis where a p ≤ 0.05 compared to PBS. No significant differences in stride length were detected. (GIF 27 kb)

11481_2011_9269_MOESM1_ESM.tif (1.6 mb)
High resolution image (TIFF 1623 kb)
11481_2011_9269_Fig6_ESM.gif (8 kb)
Supplemental Fig. 2

MPTP-induced affect on syntactic grooming. One week after PBS or MPTP treatment (four injections of 18 mg/kg/injection of MPTP), each mouse was videotaped for 10 min and later scored by an observer, blinded to treatment. Significant difference between means was determined by Student’s t test where a p ≤ 0.05. The number of completed syntactic grooming chains in MPTP-intoxicated mice trended below those observed in PBS-injected controls (p = 0.15). (GIF 8 kb)

11481_2011_9269_MOESM2_ESM.tif (2 mb)
High resolution image (TIFF 1999 kb)
Supplemental Video

Examples of syntactic grooming in PBS-treated and MPTP-intoxicated mice, 7 days post-treatment. (MP4 3727 kb)


  1. Aldridge JW, Berridge KC (1998) Coding of serial order by neostriatal neurons: a “natural action” approach to movement sequence. J Neurosci 18:2777–2787PubMedGoogle Scholar
  2. Aldridge JW, Berridge KC, Rosen AR (2004) Basal ganglia neural mechanisms of natural movement sequences. Can J Physiol Pharmacol 82:732–739PubMedCrossRefGoogle Scholar
  3. Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE (2008) Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS ONE 3:e2740PubMedCrossRefGoogle Scholar
  4. Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, Nemachek C, Green SR, Przedborski S, Gendelman HE (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 101:9435–9440PubMedCrossRefGoogle Scholar
  5. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455PubMedCrossRefGoogle Scholar
  6. Berridge KC (1989) Progressive degradation of serial grooming chains by descending decerebration. Behav Brain Res 33:241–253PubMedCrossRefGoogle Scholar
  7. Berridge KC, Fentress JC, Parr H (1987) Natural syntax rules control action sequence of rats. Behav Brain Res 23:59–68PubMedCrossRefGoogle Scholar
  8. Berridge KC, Aldridge JW, Houchard KR, Zhuang X (2005) Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette’s. BMC Biol 3:4PubMedCrossRefGoogle Scholar
  9. Crawley JN (2007) What’s wrong with my mouse?: Behavioral phenotyping of transgenic and knockout mice. Wiley, HobokenGoogle Scholar
  10. Crawley JN, Paylor R (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 31:197–211PubMedCrossRefGoogle Scholar
  11. Cromwell HC, Berridge KC (1996) Implementation of action sequences by a neostriatal site: a lesion mapping study of grooming syntax. J Neurosci 16:3444–3458PubMedGoogle Scholar
  12. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909PubMedCrossRefGoogle Scholar
  13. Fredriksson A, Archer T (1994) MPTP-induced behavioural and biochemical deficits: a parametric analysis. J Neural Transm Park Dis Dement Sect 7:123–132PubMedCrossRefGoogle Scholar
  14. Hall (1934) Emotional behavior in the rat. 1. Defecation and urination as measures of individual differences in emotionality. J Comp Physiol 18:385–403Google Scholar
  15. Heikkila RE, Hess A, Duvoisin RC (1984) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice. Science 224:1451–1453PubMedCrossRefGoogle Scholar
  16. Hirst SJ, Ferger B (2008) Systemic proteasomal inhibitor exposure enhances dopamine turnover and decreases dopamine levels but does not affect MPTP-induced striatal dopamine depletion in mice. Synapse 62:85–90PubMedCrossRefGoogle Scholar
  17. Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2:141–151PubMedCrossRefGoogle Scholar
  18. Jackson-Lewis V, Jakowec M, Burke RE, Przedborski S (1995) Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurodegeneration 4:257–269PubMedCrossRefGoogle Scholar
  19. Jones BJ, Roberts DJ (1968) The quantiative measurement of motor inco-ordination in naive mice using an accelerating rotarod. J Pharm Pharmacol 20:302–304PubMedCrossRefGoogle Scholar
  20. Jurkowski AJS, Stacy M (2005) Classification and clinical features of movement disorders. In: LeDoux M (ed) Animal Models of Movement Disorders. Elsevier Academic Press, Burlington, pp 1–12CrossRefGoogle Scholar
  21. Keshet GI, Tolwani RJ, Trejo A, Kraft P, Doyonnas R, Clayberger C, Weimann JM, Blau HM (2007) Increased host neuronal survival and motor function in BMT Parkinsonian mice: involvement of immunosuppression. J Comp Neurol 504:690–701PubMedCrossRefGoogle Scholar
  22. LeDoux MS (2005) Animal models of movement disorders. Elsevier Academic Press, BurlingtonGoogle Scholar
  23. Luchtman DW, Shao D, Song C (2009) Behavior, neurotransmitters and inflammation in three regimens of the MPTP mouse model of Parkinson’s disease. Physiol Behav 98:130–138PubMedCrossRefGoogle Scholar
  24. Meredith GE, Kang UJ (2006) Behavioral models of Parkinson’s disease in rodents: a new look at an old problem. Mov Disord 21:1595–1606PubMedCrossRefGoogle Scholar
  25. Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ (2008) Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat Disord 14(Suppl 2):S112–115PubMedCrossRefGoogle Scholar
  26. Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, Turnquist P, Vuckovic M, Fisher BE, Togasaki DM, Jakowec MW (2007) Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosci 27:5291–5300PubMedCrossRefGoogle Scholar
  27. Przedborski S, Jackson-Lewis V, Naini AB, Jakowec M, Petzinger G, Miller R, Akram M (2001) The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 76:1265–1274PubMedCrossRefGoogle Scholar
  28. Rousselet E, Joubert C, Callebert J, Parain K, Tremblay L, Orieux G, Launay JM, Cohen-Salmon C, Hirsch EC (2003) Behavioral changes are not directly related to striatal monoamine levels, number of nigral neurons, or dose of parkinsonian toxin MPTP in mice. Neurobiol Dis 14:218–228PubMedCrossRefGoogle Scholar
  29. Rozas G, Guerra MJ, Labandeira-Garcia JL (1997) An automated rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism. Brain Res Brain Res Protoc 2:75–84PubMedCrossRefGoogle Scholar
  30. Rozas G, Lopez-Martin E, Guerra MJ, Labandeira-Garcia JL (1998) The overall rod performance test in the MPTP-treated-mouse model of Parkinsonism. J Neurosci Meth 83:165–175CrossRefGoogle Scholar
  31. Schwarting RK, Sedelis M, Hofele K, Auburger GW, Huston JP (1999) Strain-dependent recovery of open-field behavior and striatal dopamine deficiency in the mouse MPTP model of Parkinson’s disease. Neurotox Res 1:41–56PubMedCrossRefGoogle Scholar
  32. Sedelis M, Hofele K, Auburger GW, Morgan S, Huston JP, Schwarting RK (2000) MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. Behav Genet 30:171–182PubMedCrossRefGoogle Scholar
  33. Seniuk NA, Tatton WG, Greenwood CE (1990) Dose-dependent destruction of the coeruleus-cortical and nigral-striatal projections by MPTP. Brain Res 527:7–20PubMedCrossRefGoogle Scholar
  34. Sonsalla PK, Heikkila RE (1986) The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. Eur J Pharmacol 129:339–345PubMedCrossRefGoogle Scholar
  35. Sundstrom E, Fredriksson A, Archer T (1990) Chronic neurochemical and behavioral changes in MPTP-lesioned C57BL/6 mice: a model for Parkinson’s disease. Brain Res 528:181–188PubMedCrossRefGoogle Scholar
  36. Taylor JL, Rajbhandari AK, Berridge KC, Aldridge JW (2010) Dopamine receptor modulation of repetitive grooming actions in the rat: potential relevance for Tourette syndrome. Brain Res 1322:92–101PubMedCrossRefGoogle Scholar
  37. Tillerson JL, Miller GW (2003) Grid performance test to measure behavioral impairment in the MPTP-treated-mouse model of parkinsonism. J Neurosci Meth 123:189–200CrossRefGoogle Scholar
  38. Tillerson JL, Caudle WM, Reveron ME, Miller GW (2002) Detection of behavioral impairments correlated to neurochemical deficits in mice treated with moderate doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Exp Neurol 178:80–90PubMedCrossRefGoogle Scholar
  39. Weydt P, Hong SY, Kliot M, Moller T (2003) Assessing disease onset and progression in the SOD1 mouse model of ALS. NeuroReport 14:1051–1054PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jessica A. L. Hutter-Saunders
    • 1
  • Howard E. Gendelman
    • 1
    • 2
    Email author
  • R. Lee Mosley
    • 1
  1. 1.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.University of Nebraska Medical Center, 985930 Nebraska Medical CenterOmahaUSA

Personalised recommendations