Using a bilateral 6-hydroxydopamine lesion to mimic motor and non-motor symptoms of Parkinson’s disease in rats

E. C. Mann¹, P. Atkinson², S. Duty¹. ¹Wolfson Centre for Age-Related Diseases, King’s College London, London, United Kingdom, ²Eisai Co. Ltd, Hatfield, United Kingdom.

Introduction: Parkinson’s disease (PD) is a neurodegenerative disease that affects approximately 1% of people over 50. Research commonly focuses on the motor aspects of the disease (e.g. bradykinesia and tremor), but patients often report the non-motor aspects to be more troublesome and these are poorly controlled with current drugs (1). There is no well established animal model of the non-motor signs to permit either their mechanistic investigation or the potential of novel therapeutic interventions. This study therefore aimed to explore the expression of non-motor signs in a widely used rat model of the motor aspects of early stage PD.

Method: Male Sprague Dawley rats were given sham (n=10) or partial, bilateral, nigrostriatal lesions (n=10) by intrastriatal injection of 12μg 6-hydroxydopamine (6-OHDA) in 4μl sterile saline with 0.2% ascorbate (injection co-ordinates: AP+0.2, ML±3 from bregma and DV-5.5 from skull surface). Rats underwent a variety of behavioural tests to assess known parkinsonian non-motor signs of anxiety, anhedonia, cognition and motor impairment. Animals were perfused 6 weeks post lesion to fix brain tissue for immunohistochemistry.

Results: 6-OHDA-treated rats showed a significant (p<0.001) and consistent nigrostriatal lesion of 67% ± 2.5% and accompanying fine motor deficits in the rotarod test at week 1, (23% reduction from baseline latency to fall, p<0.05 compared with sham) week 3 (56% reduction, p<0.01) and week 5 (54% reduction, p<0.05) post lesion. In addition, compared to sham controls, lesioned animals showed significant anxious behavior in the open field (reduction of rearing, p<0.05 compared to sham) and elevated plus maze (reduced entry into open arms p<0.05 compared to sham), but no cognitive deficit (p=0.44) in the Morris water maze. The sucrose preference test for anhedonia showed the opposite response to that expected: bilaterally lesioned rats consumed significantly more 0.8% sucrose solution than sham lesioned rats (121% ± 2% consumed over 48 hours compared with sham, p<0.01).

Conclusions: Rats bearing a partial, bilateral, nigrostriatal lesion display similar non-motor symptoms to those commonly reported by people with early stage PD. Although this model may benefit from some additional tests (e.g. of gut motility), it may prove suitable to explore the underlying mechanisms of these non-motor effects and examine the benefits of potential therapeutics on both motor and non-motor aspects of PD.

References:

1. Schapira AHV et al. (2017). Nat Rev Neurosci 18: 435-450.