Comparison of rating scales used to evaluate l-DOPA-induced dyskinesia in the 6-OHDA lesioned rat
Highlights
► Dyskinesia, stereotypy and rotation are distinct l-DOPA-induced behaviours. ► Published AIM rating methods vary in sensitivity to AIM development and pharmacological agents. ► The shape of the testing environment did not affect any behavioural measure.
Introduction
l-DOPA remains the most effective therapy in the management of the motor symptoms of Parkinson's disease (PD). However, its long-term utility is curtailed by the development of disabling side effects termed l-DOPA-induced dyskinesia (LID). These are choreic and dystonic abnormal and involuntary movements (AIM) affecting mainly the upper body, face and extremities (Barbeau, 1969). The appearance of LID affects up to 90% of patients within 10 years of chronic exposure to l-DOPA and is progressive and irreversible (Ahlskog and Muenter, 2001). Given that l-DOPA is still a necessity in the treatment of advanced PD, reducing or avoiding LID is a key objective in the management of PD motor symptoms. In clinical practice, LIDs are assessed using observational rating scales based on clinical examination, patient historical self-evaluation or both and to this end, over 15 different scales have been used since the 1970s. However, recent limited success of new anti-dyskinesiogenic agents in the clinic has highlighted the variability in evaluation techniques. The opinion has emerged that a general consensus is required to identify and use a single reliable, well validated dyskinesia rating scale, to permit greater comparability between clinical trials, and to increase the validity of their findings (Colosimo et al., 2010, Goetz et al., 2011).
The same issues of reliability and validation are encountered in preclinical research, a factor, which may also contribute to the lack of success in translational studies. Thus, in the MPTP-treated primate model of PD, LIDs are typically evaluated using rating scales adapted from the human yardstick, and there is a similar debate over both the validity of the various scales and the need for greater consistency between laboratories (Fox et al., 2012, Jenner, 2003, Jolkkonen et al., 1995, Pearce et al., 1995, Petzinger et al., 2001).
More recently, similar developments have taken place with the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rodent (Cenci et al., 1998, Lundblad et al., 2002, Lundblad et al., 2005, Maries et al., 2006, Smith et al., 2012b, Steece-Collier et al., 2003, Winkler et al., 2002). The initial studies created intense debate (for detail see Cenci et al., 2002), in part stemming from early studies, which showed a causal link between over-stimulation of dopaminergic system and stereotypic behaviours in rodents (Fog, 1969, Randrup et al., 1963). Motor effects induced by l-DOPA in dopamine-denervated rats were therefore first simply described as stereotypies (Ervin et al., 1977). However, in 1998, Cenci and colleagues demonstrated that the animals also exhibit distinct abnormal dystonic and choreic movements comparable to the abnormal movements observed in PD patients or non-human primates when repeatedly exposed to l-DOPA. The first AIM scale for rodents described forelimb movements, orolingual and jaw movements, axial contortion and rotational locomotion; each rated based on the duration each was present during an observation phase (Cenci et al., 1998). In a later adaptation, a second parameter was added to each movement type, an amplitude score, which considers the extent of the movement, differentiating, for example, between small but clearly present movements of the forelimb and wrist and larger, more dystonic-like movements involving the whole shoulder (Winkler et al., 2002). In parallel, Steece-Collier and colleagues developed a similar scoring scale, which distinguished between a greater number of movement elements (Maries et al., 2006, Steece-Collier et al., 2003). Thus far, all three rating scales have been used to follow the development of AIM and explore the underlying mechanisms whilst also evaluating the propensity of new agents to reduce LID both by the authors and adapted by other groups (Lundblad et al., 2002, Monville et al., 2005, Munoz et al., 2009, Rylander et al., 2010, Taylor et al., 2005). Importantly, the first AIM scale is the only one that has ever been extensively validated with pharmacological agents known to reduce LID in primate models and in the clinic (Lundblad et al., 2002). Furthermore, no studies comparing these different scoring methodologies have been carried out, nor their direct comparison with classical rating measures of stereotypy (Creese and Iversen, 1973).
This paper evaluates the reliability of the 3 AIM behavioural rating scales and their associated methodologies in the assessment of the effects of repeated l-DOPA administration, and compares them to the most commonly used classical stereotypy scale (Creese and Iversen, 1973). Furthermore, we examine how these scales reflect the effects of dopamine receptor antagonists and the only anti-dyskinesia agent available in the clinic, amantadine.
Section snippets
6-Hydroxydopamine lesion
28 female Sprague–Dawley rats (Harlan UK), weighing 220–250 g at the start of the experiment were housed 2–4 per cage with ad libitum access to food and water. The experiment was approved by local ethical review at Cardiff University and conducted in accordance with the UK Animal (Scientific Procedure) Act 1996. 6-OHDA HBr was delivered directly into the right median forebrain bundle, as described in detail by Torres et al. (2011). Briefly, the rats were anaesthetised with 2–3% Isoflurane (IVAK,
Rotational behaviour
On the first day of l-DOPA administration the rats rotated at very low levels, with only a slight contralateral preference. Over the course of chronic administration the rotational response to 6 mg/kg l-DOPA remained relatively stable but maintained an overall contralateral bias. When the l-DOPA dose was increased to 12 mg/kg at week 6 the net rotations significantly increased in the contralateral direction (Fig. 1F; F9,243 = 40.52, p < 0.0001, Bonferroni post-hoc: p < 0.001) and continued to increase
Discussion
The disability caused by the development of abnormal movements in response to l-DOPA has stimulated significant research into novel therapeutics that can either alleviate the behaviours or replace l-DOPA and avoid their inception and into their pathology, in both patients and animal models. Despite this extensive research program, rating the movements is still heavily dependent upon subjective rating scales based on direct visual observation, be it in the clinic, primate or rodent models (Fahn
Conclusion
To ensure that AIM scoring in the rodent 6-OHDA lesioned models becomes a highly standardised tool, fully validated scales to produce robust and comparable data are a must. In the present experiment, we found that all published rodent scales do reflect the effects of l-DOPA and pharmacological reductions in LID. Nevertheless, it remains a fundamental of behavioural experimentation that individual assessment protocols revalidate scales in their own hands before any modifications are made and
Acknowledgments
The authors declare no conflicts of interest. We acknowledge funding from the Medical Research Council and the European Union (EC contract number 222918 REPLACES FP7 — Thematic priority HEALTH)
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2019, NeuropharmacologyCitation Excerpt :This choice has obvious ramifications as to the cost of running the study, most critically in terms of number of animals but also related to the amount of test item required, staffing and total research budget considerations. Detailed descriptions of the principal rodent and primate models of LID are reported and have been reviewed elsewhere (Breger et al., 2013; Fox and Brotchie, 2010; Jenner, 2003, 2009; Johnston and Lane, 2011; Morin et al., 2014) but are summarised below. The most widely-employed rodent models of LID are based upon a unilateral 6-hydroxydopamine (6-OHDA)-evoked unilateral lesion of the medial forebrain bundle, in rats or mice, which typically leads to a severe (>85% loss of striatal dopamine) and a stable lesion of the nigrostriatal tract (Ungerstedt and Arbuthnott, 1970).
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2017, NeuroscienceCitation Excerpt :While these LFPs have been implicated in PD it is unknown how they change as LIDs develop (Brown et al., 2001; Williams et al., 2002; Brown and Williams, 2005). A significant challenge to resolving these issues is that prior studies have human raters score abnormal involuntary movements as a measure of LIDs in rodents (Lundblad et al., 2002; Winkler et al., 2002; Smith et al., 2011; Breger et al., 2013). In this method, humans grade axial, limb, and orofacial dyskinesias over a 1- to 2-min window every several minutes (Lundblad et al., 2005; Cenci and Lundblad, 2007; Santini et al., 2007).