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The role of anxiety in the development of levodopa-induced dyskinesias in an animal model of Parkinson’s disease, and the effect of chronic treatment with the selective serotonin reuptake inhibitor citalopram

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Abstract

Introduction

Levodopa-induced dyskinesia (LID) is an inevitable complication of the long-term treatment of Parkinson’s disease (PD) with levodopa. In a rat model of LID, we observed that animals of almost identical genetic but slightly different environmental backgrounds displayed a very different profile in terms of their development and severity of LID.

Materials and methods

We hypothesised that this heterogeneity can be attributed to different levels of anxiety in individual animals. We evaluated the basal anxiety level of rats in this study using the elevated plus maze (EPM), open field (OF) test, and plasma corticosterone level. These animals then received unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway after which they were primed to develop LID. Finally, we manipulated the anxiety level of these animals by citalopram treatment over a 9-week period before they were killed.

Results

Although we could not establish an association between the anxiety level of rats with either the onset or severity of LID, our results showed that citalopram was able to mediate a partial alleviation in LID after chronic treatment, and the extent of recovery was negatively correlated to the anxiety measures of individual animals. Furthermore, this citalopram-mediated LID recovery appeared to be independent of any changes in striatal cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and cyclin-dependent kinase 5 (Cdk5) system, in contrast to our previous studies with fetal ventral mesencephalon transplants. However, chronic citalopram treatment almost completely abolished the expression of serotonin receptor 1B (5HT1B) in the striatum in animals exhibiting LID recovery.

Conclusions

These results indicate a novel association of serotonin receptors in the development of LID and contributes to the evidence that the serotonergic system may play an important role in such movements.

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Acknowledgement

WLK is supported by the Oversea Research Studentship and the Cambridge Commonwealth Trust. We would like to thank Prof. Trevor Robbins for his critical comments on this study, and Prof. Joe Herbert and Mrs. Helen Shiers for their assistance in plasma corticosteroid analysis.

Disclosure

The authors declare that no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research and professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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Authors and Affiliations

  1. Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK

    Wei-Li Kuan, Jing-Wei Zhao & Roger A. Barker

  2. Department of Neurology, Addenbrookes Hospital, Cambridge, CB2 2QQ, UK

    Roger A. Barker

  3. Edith Cowan University, Perth, Australia

    Roger A. Barker

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  1. Wei-Li Kuan
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  2. Jing-Wei Zhao
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Correspondence to Wei-Li Kuan.

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Kuan, WL., Zhao, JW. & Barker, R.A. The role of anxiety in the development of levodopa-induced dyskinesias in an animal model of Parkinson’s disease, and the effect of chronic treatment with the selective serotonin reuptake inhibitor citalopram. Psychopharmacology 197, 279–293 (2008). https://doi.org/10.1007/s00213-007-1030-6

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