Elsevier

Experimental Neurology

Volume 333, November 2020, 113427
Experimental Neurology

Research paper
The antiparkinson drug ropinirole inhibits movement in a Parkinson's disease mouse model with residual dopamine neurons

https://doi.org/10.1016/j.expneurol.2020.113427Get rights and content

Highlights

  • Ropinirole is often used for early-middle stage Parkinson's disease (PD).

  • D2-like agonism may activate D2 autoreceptors on the residual dopamine neurons.

  • Systemic ropinirole inhibits motor activity in early-middle stage PD mouse model.

  • Striatal ropinirole injection stimulates motor activity in same PD mouse model.

  • Systemic ropinirole stimulates motor activity in late stage PD mouse model.

Abstract

The dopamine (DA) D2-like receptor (D2R) agonist ropinirole is often used for early and middle stage Parkinson's disease (PD). However, this D2-like agonism-based strategy has a complicating problem: D2-like agonism may activate D2 autoreceptors on the residual DA neurons in the PD brain, potentially inhibiting these residual DA neurons and motor function. We have examined this possibility by using systemic and local drug administration in transcription factor Pitx3 null mutant (Pitx3Null) mice that mimic the DA denervation in early and middle stage PD and in DA neuron tyrosine hydroxylase (TH) gene knockout (KO) mice that mimic the severe DA loss in late stage PD. We found that in Pitx3Null mice with residual DA neurons and normal mice with normal DA system, systemically injected ropinirole inhibited locomotion, whereas bilateral dorsal striatal-microinjected ropinirole stimulated movement in Pitx3Null mice; bilateral microinjection of ropinirole into the ventral tegmental area also inhibited movement in Pitx3Null mice; we further determined that ropinirole inhibited nigral DA neuron spike firing in WT mice. In contrast, both systemically and striatum-locally administered ropinirole increased movements in TH KO mice, but produced relatively more dyskinesia than L-dopa. Although requiring confirmation in non-human primates and PD patients, these data suggest that while activating D2-like receptors in striatal projection neurons and hence stimulating movements, D2-like agonists can inhibit residual DA neurons and cause akinesia when the residual DA neurons and motor functions are still substantial, and this motor-inhibitory effect disappears when almost all DA neurons are lost such as in late stage PD.

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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