Elsevier

Neuroscience

Volume 88, Issue 2, January 1999, Pages 617-628
Neuroscience

Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson's disease: studies on medial forebrain bundle and striatal lesions

https://doi.org/10.1016/S0306-4522(98)00217-6Get rights and content

Abstract

Deficits in forepaw adjusting steps in rats have been proposed as a non-drug induced model of the akinesia associated with Parkinson's disease. The present study examined the relationship between contralateral forepaw adjusting steps and dopamine depletion after medial forebrain bundle lesions with 6-hydroxydopamine. Depletion of striatal dopamine by >80% resulted in dramatic reductions in the ability of rats to make adjusting steps, but rats with <80% dopamine depletion had no detectable deficit. The deficit in forepaw adjusting steps was evident by three days after lesions and did not recover for up to 13 weeks. Compared to apomorphine-induced rotation, the deficit in adjusting steps was evident at milder dopamine depletion. Discrete striatal lesions were also utilized to localize the striatal subregions that mediate forepaw adjusting steps. Forepaw adjusting steps were reduced after lesions of dorsolateral, ventrolateral, or ventrocentral striatum, but not after lesions of dorsomedial, dorsocentral, or ventromedial striatum. The reductions in adjusting steps after the discrete striatal lesions were not as severe as after medial forebrain bundle lesions. Furthermore, none of the discrete striatal lesions resulted in rotation after apomorphine administration, although a few resulted in increase in amphetamine-induced rotation. Administration of l-3,4-dihydroxyphenylalanine partially reversed the reductions of forepaw adjusting steps in both sets of lesion experiments.

Together, these results suggest that forepaw adjusting step deficits in the rat provide a good model for the akinesia of Parkinson's disease both in medial forebrain bundle and striatal lesions, and would be a useful tool for investigating the efficacy of various therapeutic strategies.

Section snippets

Animals

The following in vivo protocols were approved by the Institutional Animal Care and Use Committee of The University of Chicago. All efforts were made to minimize animal suffering, to reduce the number of animals used, and to utilize alternatives to in vivo techniques. Female Fischer 344 rats (n=48), weighing 150–200 g were used for the first set of experiments with MFB lesions, and female Sprague–Dawley rats (n=35), weighing 150–200 g were used for the second set of experiments with striatal

Comparison of forepaw adjusting step deficits to dopamine depletion

To examine the relationship between the degree of dopamine depletion and contralateral forehand adjusting steps, the degree of dopamine depletion was correlated with the average number of contralateral forehand adjusting steps at two weeks after the lesions. Forehand adjusting steps appeared to have an all-or-none relationship with dopamine depletion. That is, the deficit in adjusting steps appeared dramatically at a threshold of approximately 80% dopamine depletion. The eight rats with less

Discussion

This study focused on deficits of forepaw adjusting steps as simplified measure of akinesia in an animal model of PD. Thus, deficits in forepaw adjusting steps were characterized both as a function of the degree of dopamine depletion after MFB lesions and as a function of the striatal subregions involved in the movement. The present results clearly indicate that testing of forepaw adjusting steps is a simple and quantitative measure, and can be used to evaluate the potential efficacy of

Conclusions

In summary, deficits in forepaw adjusting steps provide a simple and consistent behavior phenomenologically similar to akinesia in PD. The relationship between the amount of dopamine loss and the appearance of deficits is analogous to that for parkinsonian symptoms and provides a valuable model of parkinsonian akinesia. Furthermore, the stepping model has several advantages over drug-induced rotation and other models for examining various therapeutic strategies. Although the deficit occurs

Acknowledgements

This research was supported by PHS Grant R29 NS32080, Parkinson's Disease Foundation Junior Faculty Award, United Parkinson Foundation/the H.G. and Catharine Lieneman Memorial Fund, National Parkinson Foundation, Brain Research Foundation (UJK), T32 DA07255 (SRW), and Yonsei University Faculty Research Funds (JWC). We thank Nicole Nemeth and Mildred Bahn for their expert technical assistance, and Dr Michael Cousins for his critical comments on the manuscript.

References (45)

  • C.S Lee et al.

    Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-OHDA in the rat

    Neuroscience

    (1996)
  • H Moukhles et al.

    Behavioural recovery of rats grafted with dopamine cells after partial striatal dopaminergic depletion in a conditioned reaction-time task

    Neuroscience

    (1994)
  • D.A Perese et al.

    A 6-hydroxydopamine-induced selective parkinsonian rat model

    Brain Res.

    (1989)
  • M Pisa

    Motor functions of the striatum in the rat: critical role of the lateral region in tongue and forelimb reaching

    Neuroscience

    (1988)
  • M Pisa et al.

    Regionally selective roles of the rat's striatum in modality-specific discrimination learning and forelimb reacing

    Behav. Brain Res.

    (1990)
  • T.E Robinson et al.

    Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats

    Brain Res.

    (1988)
  • K.E Sabol et al.

    Dopamine depletion in a striatal subregion disrupts performance of a skilled motor task in the rat

    Brain Res.

    (1985)
  • J.D Salamone et al.

    The role of brain dopamine in response initation: effects of haloperidol and regionally specific dopamine depletions on the local rate of instrumental responding

    Brain Res.

    (1993)
  • J.D Salamone et al.

    Ventrolateral striatal dopamine depletions impair feeding and food handling in rats

    Pharmac. Biochem. Behav.

    (1993)
  • H Sauer et al.

    Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat

    Neuroscience

    (1994)
  • R.K.W Schwarting et al.

    The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments

    Prog. Neurobiol.

    (1996)
  • I.Q Whishaw et al.

    Dopamine and skilled limb use in the rat: more severe bilateral impairments follow substantia nigra than sensorimotor cortex 6-hydroxydopamine injection

    Behav. Brain Res.

    (1992)
  • Cited by (217)

    View all citing articles on Scopus
    1

    Present address: Department of Neurosurgery, Yonsei University College of Medicine, CPO BOX 8044, Seoul, Korea

    2

    Present address: Department of Psychiatry, The University of Chicago, U.S.A.

    View full text