Neurotoxicity Research

, Volume 17, Issue 3, pp 287–298 | Cite as

6-Hydroxydopamine Lesions in the Rat Neostriatum Impair Sequential Learning in a Serial Reaction Time Task

  • Moritz Thede Eckart
  • Moriah Christina Huelse-Matia
  • Rebecca S. McDonald
  • Rainer K.-W. Schwarting


Sequential behavior has been intensively investigated in humans using so-called serial reaction time tasks (SRTT), in which visual stimuli are either presented in a random or sequential order. Typically, when the stimulus presentation follows a previously learned sequential order, reaction times are decreased compared to random stimulus presentation and become partly automated. A vast amount of SRTT findings indicates that sequential learning and performance seem to be mediated amongst others by the basal ganglia—especially the striatum—and the neurotransmitter dopamine therein. In this study we used an operant rat version of the human four choice SRTT to investigate the effect of bilateral neostriatal dopamine lesions induced by 6-hydroxydopamine on sequential learning. The rats’ task was to respond rapidly to illuminated holes by nose-poking into them. During extensive training, the position of the illuminated hole followed a 12-item sequence. The outcome of this sequential training was also investigated in two tests, namely an interference test, where stimulus presentation switched between this sequential and a pseudo random order every five minutes, and a violation test, in which only one sequence item was eventually skipped. The neurotoxic lesions, which was placed before the start of training, led to the expected sub-total dopamine depletions (i.e. residual levels around 34–56% of controls), especially in the medial neostriatum. These lesions did not lead to general motor deficits in a catalepsy task, but moderate deficits in locomotion in an activity box, which largely recovered with time after lesion. In the SRTT, rats with lesions showed impaired learning, that is, less response accuracy and slower reaction times than the control group. During a subsequent test with alternating phases of sequential and random stimulus presentations, reaction times and accuracy of the control group were superior during sequential as compared to random stimulus phases. In the lesion group, only a moderate advantage in accuracy was observed. In the violation test, another outcome measure, the control group showed an expected increase in reaction times on the violated positions. By contrast, the lesion group showed no such increase, which indicates less automation of sequential behavior in these animals. For one, these findings support previous evidence in showing that neostriatal dopamine plays an important role for instrumental behavior, in general. Furthermore, and most importantly, they suggest that dopaminergic-striatal networks also play an important role in sequential behavior, especially its acquisition.


Neurotoxic lesion 6-OHDA Dopamine Dorsal striatum Parkinson’s disease 







Fixed ratio


Parkinson’s disease


Reaction time


Serial reaction time task



This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, Schw 559/6-1). Moritz Thede Eckart is a member of the DFG graduate program “NeuroAct”.


  1. Abdi H (2007) Bonferroni and Sidak corrections for multiple comparisons. In: Salkind NJ (ed) Encyclopedia of measurement and statistics. Sage, Thousand Oaks, CAGoogle Scholar
  2. Amalric M, Moukhles H, Nieoullon A, Daszuta A (1995) Complex deficits on reaction time performance following bilateral intrastriatal 6-OHDA infusion in the rat. Eur J Neurosci 7:972–980CrossRefPubMedGoogle Scholar
  3. Antoniou K, Papadopoulou-Daifotis Z, Kafetzopoulos E (1998) Differential alterations in basal and D-amphetamine-induced behavioural pattern following 6-OHDA or ibotenic acid lesions into the dorsal striatum. Behav Brain Res 97:13–28CrossRefPubMedGoogle Scholar
  4. Ashby FG, Ennis JM, Spiering BJ (2007) A neurobiological theory of automaticity in perceptual categorization. Psychol Rev 114:632–656CrossRefPubMedGoogle Scholar
  5. Badgaiyan RD, Fischman AJ, Alpert NM (2007) Striatal dopamine release in sequential learning. Neuroimage 38:549–556CrossRefPubMedGoogle Scholar
  6. Branchi I, D’Andrea I, Armida M, Cassano T, Pezzola A, Potenza RL, Morgese MG, Popoli P, Alleva E (2008) Nonmotor symptoms in Parkinson’s disease: investigating early-phase onset of behavioral dysfunction in the 6-hydroxydopamine-lesioned rat model. J Neurosci Res 86:2050–2061CrossRefPubMedGoogle Scholar
  7. Cass WA, Peters LE, Smith MP (2005) Reductions in spontaneous locomotor activity in aged male, but not female, rats in a model of early Parkinson’s disease. Brain Res 1034:153–161CrossRefPubMedGoogle Scholar
  8. Courtiere A, Hardouin J, Locatelli V, Turle-Lorenzo N, Amalric M, Vidal F, Hasbroucq T (2005) Selective effects of partial striatal 6-OHDA lesions on information processing in the rat. Eur J Neurosci 21:1973–1983CrossRefPubMedGoogle Scholar
  9. Da Cunha C, Wietzikoski EC, Dombrowski P, Bortolanza M, Santos LM, Boschen SL, Miyoshi E (2009) Learning processing in the basal ganglia: a mosaic of broken mirrors. Behav Brain Res 199:157–170CrossRefPubMedGoogle Scholar
  10. Domenger D, Schwarting RK (2005) Sequential behavior in the rat: a new model using food-reinforced instrumental behavior. Behav Brain Res 160:197–207CrossRefPubMedGoogle Scholar
  11. Domenger D, Schwarting RK (2006) The serial reaction time task in the rat: effects of D1 and D2 dopamine-receptor antagonists. Behav Brain Res 175:212–222CrossRefPubMedGoogle Scholar
  12. Domenger D, Schwarting RK (2007) Sequential behavior in the rat: role of skill and attention. Exp Brain Res 182:223–231CrossRefPubMedGoogle Scholar
  13. Domenger D, Schwarting RK (2008) Effects of neostriatal 6-OHDA lesion on performance in a rat sequential reaction time task. Neurosci Lett 444:212–216CrossRefPubMedGoogle Scholar
  14. Doyon J, Ungerleider LG (2002) Functional anatomy of motor skill learning. In: Squire LR, Schachter DL (eds) Neuropsychology of memory. Guilford, New York, pp 225–238Google Scholar
  15. Doyon J, Song AW, Karni A, Lalonde F, Adams MM, Ungerleider LG (2002) Experience-dependent changes in cerebellar contributions to motor sequence learning. Proc Natl Acad Sci USA 99:1017–1022CrossRefPubMedGoogle Scholar
  16. Faure A, Haberland U, Conde F, El Massioui N (2005) Lesion to the nigrostriatal dopamine system disrupts stimulus-response habit formation. J Neurosci 25:2771–2780CrossRefPubMedGoogle Scholar
  17. Ferro MM, Bellissimo MI, Anselmo-Franci JA, Angellucci ME, Canteras NS, Da Cunha C (2005) Comparison of bilaterally 6-OHDA- and MPTP-lesioned rats as models of the early phase of Parkinson’s disease: histological, neurochemical, motor and memory alterations. J Neurosci Methods 148:78–87CrossRefPubMedGoogle Scholar
  18. Graybiel AM (1998) The basal ganglia and chunking of action repertoires. Neurobiol Learn Mem 70:119–136CrossRefPubMedGoogle Scholar
  19. Howell DC (2002) Statistical methods for psychology. Duxbury, Pacific Grove, CAGoogle Scholar
  20. Jinnah HA, Hess EJ (2003) Assessment of movement disorders in rodents. In: LeDoux M (ed) Animal models of movement disorders. Elsevier, New York, pp 55–71Google Scholar
  21. Kirik D, Rosenblad C, Bjorklund A (1998) Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 152:259–277CrossRefPubMedGoogle Scholar
  22. Lindner MD, Plone MA, Francis JM, Blaney TJ, Salamone JD, Emerich DF (1997) Rats with partial striatal dopamine depletions exhibit robust and long-lasting behavioral deficits in a simple fixed-ratio bar-pressing task. Behav Brain Res 86:25–40CrossRefPubMedGoogle Scholar
  23. Nissen MJ, Bullemer P (1987) Attentional requirements of learning: evidence from performance measures. Cogn Psychol 19:1–32CrossRefGoogle Scholar
  24. Packard MG, Knowlton BJ (2002) Learning and memory functions of the Basal Ganglia. Annu Rev Neurosci 25:563–593CrossRefPubMedGoogle Scholar
  25. Paxinos G, Watson C (2005) The rat brain in stereotactic coordinates. Elsevier, LondonGoogle Scholar
  26. Reed J, Johnson P (1994) Assessing implicit learning with indirect tests: determinating what is learned about sequence structure. J Exp Psychol 20:585–594Google Scholar
  27. Robbins TW, Giardini V, Jones GH, Reading P, Sahakian BJ (1990) Effects of dopamine depletion from the caudate-putamen and nucleus accumbens septi on the acquisition and performance of a conditional discrimination task. Behav Brain Res 38:243–261CrossRefPubMedGoogle Scholar
  28. Sandberg PR, Bunsey MD, Giordano M, Norman AB (1988) The catalepsy test: its ups and downs. Behav Neurosci 102:748–759CrossRefGoogle Scholar
  29. Scholtissen B, Deumens R, Leentjens AF, Schmitz C, Blokland A, Steinbusch HW, Prickaerts J (2006) Functional investigations into the role of dopamine and serotonin in partial bilateral striatal 6-hydroxydopamine lesioned rats. Pharmacol Biochem Behav 83:175–185CrossRefPubMedGoogle Scholar
  30. Schwarting RK (2009) Rodent models of serial reaction time tasks and their implementation in neurobiological research. Behav Brain Res 199:76–88CrossRefPubMedGoogle Scholar
  31. Siegert RJ, Taylor KD, Weatherall M, Abernethy DA (2006) Is implicit sequence learning impaired in Parkinson’s disease? A meta-analysis. Neuropsychology 20:490–495CrossRefPubMedGoogle Scholar
  32. Vandenbossche J, Deroost N, Soetens E, Kerckhofs E (2009) Does implicit learning in non-demented Parkinson’s disease depend on the level of cognitive functioning? Brain Cogn 69:194–199CrossRefPubMedGoogle Scholar
  33. Werheid K, Ziessler M, Nattkemper D, Yves von Cramon D (2003) Sequence learning in Parkinson’s disease: the effect of spatial stimulus-response compatibility. Brain Cogn 52:239–249CrossRefPubMedGoogle Scholar
  34. Wilcox RR (1987) New designs in analysis of variance. Annu Rev Psychol 38:29–60CrossRefGoogle Scholar
  35. Yin HH, Knowlton BJ, Balleine BW (2004) Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur J Neurosci 9:181–189CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Moritz Thede Eckart
    • 1
  • Moriah Christina Huelse-Matia
    • 1
  • Rebecca S. McDonald
    • 1
  • Rainer K.-W. Schwarting
    • 1
  1. 1.Department of Psychology, Experimental and Physiological PsychologyPhilipps-University of MarburgMarburgGermany

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