Research paperThe antiparkinson drug ropinirole inhibits movement in a Parkinson's disease mouse model with residual dopamine neurons
Introduction
The endogenous neurotransmitter dopamine (DA), highly concentrated in the striatum, activates primarily the highly expressed DA D1 receptors (D1Rs) and DA D2 receptors (D2Rs) in two populations of the striatal medium spiny projection neurons (hence D1-MSNs and D2-MSNs) to facilitate and stimulate motor function (Bello et al., 2017; Franco and Turner, 2012; Grillner and Robertson, 2016; Li et al., 2013; Mailman et al., 2001). Loss of DA neurons or inhibition of DA synthesis leads to loss of motor function and Parkinson's disease (PD); restoration of the brain DA level, via DA replacement therapy, restores motor function (Carlsson, 2001; Fahn, 2015; Zhou and Palmiter, 1995). DA replacement therapy for PD is traditionally achieved by L-dopa that is converted to DA in the brain (Lees et al., 2015; LeWitt and Fahn, 2016). However, largely due to the excessive fear of L-dopa-induced dyskinesias and the unfounded notion that L-dopa is toxic to DA neurons whereas D2R agonists are neuroprotective (Fahn, 2005), the D2-like agonists ropinirole and pramipexole are often advocated for and used in early and middle stage PD when the motor deficits are not severe, saving L-dopa, the most effective therapeutic agent with the least side effects due to its being an endogenous molecule in the brain, for severe motor deficits in late stage PD (Katzenschlager et al., 2008; Titova et al., 2018; Vlaar et al., 2011). However, recent clinical and basic science evidence indicates that PD duration and DA loss severity — a longer disease duration usually leads to severer DA loss (Kordower et al., 2013) — often set the stage for dyskinesias, and L-dopa only serves as a trigger and can trigger dyskinesias on the first L-dopa dosing or very quickly when DA loss is severe (Ballard et al., 1985; Cilia et al., 2014; Li and Zhou, 2013; Onofrj et al., 1998); these new data weaken or even invalidate the original rationale for using ropinirole and pramipexole that are more expensive, have more side effects and weaker therapeutic effects than L-dopa (Katzenschlager et al., 2008; Olanow et al., 2009). Furthermore, a potentially important complicating problem in the D2R agonist treatment strategy for early stage PD is that although a D2R agonist may directly stimulate D2Rs and partially mimic the effect of DA and thus stimulate motor function, D2R agonists may activate inhibitory D2 autoreceptors in DA neuron somata and axon terminals, thus inhibiting the spike firing of the residual DA neurons and the DA release from residual DA axon terminals in early and middle stage PD brains, and consequently inhibiting motor function.
Here we report our findings on ropinirole's motor-inhibiting and motor-stimulating effects, depending on the severity of DA loss in the striatum, in experimental animals, initially as a serendipitous observation.
Section snippets
Animal models
Animal care and use were in accordance with federal and local guidelines and approved by the Institutional Animal Care and Use Committee of the University of Tennessee Health Science Center (UTHSC) in Memphis, Tennessee. Four-five months old mice were used for experiments. The mice were housed in groups of 5 before implantation surgery and individually after surgery in a temperature and humidity-controlled room with the UTHSC animal facility. Mice had free access to food and water.
The
Systemic ropinirole administration inhibits movement in Pitx3Null and WT mice that have endogenous DA, but stimulates movement in TH KO mice that have no endogenous DA
Following our initial surprising observation that 1 mg/kg ropinirole inhibited locomotion in Pitx3Null mice, we started a series of experiments to solidify and expand the initial observation and determine underlying mechanism. In addition to Pitx3Null mice that have features (having considerable residual DA innervation in the striatum, ventral striatum in particular) resembling early and middle stage PD, we included WT mice as a general control and also TH KO mice to mimic late stage PD.
Discussion
The main findings of this study are that the D2-like agonist ropinirole can inhibit DA neurons and cause akinesia by inhibiting the residual DA neurons that maintain the considerable residual motor function such as in early and middle stage PD, and these motor-inhibiting effects become small and insignificant when all DA neurons are lost such as in late stage PD and motor stimulation becomes the dominant effect, raising questions about the common view that D2 agonists should be used in early
Conclusions and clinical implications
Our data obtained from PD mouse models clearly show that likely by activating the inhibitory D2 autoreceptors, ropinirole inhibits motor function when there are significant residual DA neurons that support the residual motor function such as in early-middle stage PD (Fig. 6A,B). When the residual DA neurons are no longer functionally significant such as in late stage PD, ropinirole stimulates motor function, by stimulating postsynaptic D2 receptors in the striatum (Fig. 6C). Although requiring
Author roles
Conceptualization: FMZ
Data collection: YW, SB, FMZ
Analysis: YW, SB, FMZ
Manuscript Preparation: YW, SB, MD, FMZ
Declaration of Competing Interest
The authors declare no competing financial interests.
Acknowledgements
This work was supported by NIH/NINDS grant R01NS097671. Safa Bouabid was a recipient of the University of Tennessee Neuroscience Institute FY2018 postdoctoral fellowship. The authors also thank Dr. Richard Palmiter for supplying the original tyrosine hydroxylase knockout mice.
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2021, Behavioural Brain ResearchCitation Excerpt :To date, functional studies are still conflicting regarding the involvement of DA receptors in the treatment to enhance the motor activity of PD [8]. Therefore, the important issue concerns the nature of the dopamine receptor involved in either the reversal of the motor symptoms of PD or in the production of dyskinesias [9–11]. As the main input nucleus of the basal ganglia, the striatum plays an important role in motor control and motor learning [12,13].
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These authors contributed equally to this work