The Vasomotor Response to Dopamine Is Altered in the Rat Model of l‐dopa‐Induced Dyskinesia

Abstract

A BS TRACT: Background: Levodopa (L-dopa) is the frontline treatment for motor symptoms of Parkinson's disease. However, prolonged use of L-dopa results in a motor complication known as levodopa-induced dyskinesia (LID) in~50% of patients over 5 years. Objectives: We investigated neurovascular abnormalities in a rat model of LID by examining changes in angiogenesis and dopamine-dependent vessel diameter changes. Methods: Differences in striatal and nigral angiogenesis in a parkinsonian rat model (6-OHDA lesion) treated with 2 doses of L-dopa (saline, 2, and 10 mg/kg/day subcutaneous L-dopa treatment for 22 days) by 5-bromo-2'deoxyuridine (BrdU)-RECA1 co-immunofluorescence. Difference in the vasomotor response to dopamine was examined with 2-photon laser scanning microscopy and Dodt gradient imaging. Results: We found that the 10 mg/kg L-dopa dosing regimen induced LID in all animals (n = 5) and induced significant angiogenesis in the striatum and substantia nigra. In contrast, the 2 mg/kg treatment induced LID in 6 out of 12 rats and led to linearly increasing LID severity over the 22-day treatment period, making this a promising model for studying LID progression longitudinally. However, no significantly different level of angiogenesis was observed between LID versus non-LID animals. Dopamine-induced vasodilatory responses were exaggerated only in rats that show LID-like signs compared to the rest of groups. Additionally, in juvenile rats, we showed that DA-induced vasodilation is preceded by increased Ca 2+ release in the adjacent astrocytes. Conclusion: This finding supports that astrocytic dopamine signaling controls striatal blood flow bidirectionally, and the balance is altered in LID.

Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa‐Induced Dyskinesia

“…This combination treatment was necessary to maintain moderate–severe and reproducible AIM scores over time, a prerequisite for using this model in preclinical pharmacological studies. We could not reproduce results by other groups showing that low‐dose L ‐dopa (2–3 mg/kg/day) leads to a gradual development of moderate–severe dyskinesia 12 …”

“…These failures indicate that additional efforts are needed to improve both clinical trial methodology and preclinical models in this translational area 1,6 . In particular, several authors have expressed a concern that the use of relatively high bolus doses of L ‐dopa in the experimental setting does not reflect DOPA‐sparing strategies currently used in the clinic 12,30 . Indeed, advanced stages of PD are rarely managed using L ‐dopa as a monotherapy, as other dopaminergic agents are added to achieve longer‐lasting therapeutic effects and reduce the daily L ‐dopa dose (reviewed in 1 ).…”

“…1,6 In particular, several authors have expressed a concern that the use of relatively high bolus doses of L-dopa in the experimental setting does not reflect DOPA-sparing strategies currently used in the clinic. 12,30 Indeed, advanced stages of PD are rarely managed using L-dopa as a monotherapy, as other dopaminergic agents are added to achieve longer-lasting therapeutic effects and reduce the daily L-dopa dose (reviewed in 1 ). Some of these agents (eg, DA breakdown inhibitors) are unlikely to modify neuronal signaling events elicited by the primary treatment.…”

Histological Correlates of Neuroanatomical Changes in a Rat Model of Levodopa-Induced Dyskinesia Based on Voxel-Based Morphometry

“…Previous studies have elegantly demonstrated that L-DOPA exposure modifies the brain microvasculature. For example, Booth et al (2021) recently reported that a 10 mg/kg L-DOPA dosing regimen induced significant angiogenesis in the striatum and SN, which was accompanied by a local vasomotor reaction. Similar results have been reported, including increased BBB permeability, blood vessel length, and cerebral blood flow, in L-DOPA-treated dyskinetic rats, which further indicate angiogenesis (Lindgren et al, 2009;Ohlin et al, 2011;Aljuaid et al, 2019).…”

“…Several studies using functional magnetic resonance imaging (fMRI) (Herz et al, 2016) and positron emission tomography (PET) (Rascol et al, 1998;Brooks et al, 2000) have reported that LID involves molecular changes, metabolism, and abnormal brain network connections in the cortex-striatumcortex loop. Electrophysiological and neuropathological studies have suggested that LID results from long-term adaptive brain plasticity (Belujon et al, 2010;Ohlin et al, 2011;Zheng et al, 2020), which could be attributed to neuroanatomical remodeling at the level of cells (Bortolanza et al, 2015;Mulas et al, 2016;Fletcher et al, 2020), spine and synapses (Zhang et al, 2013;Suarez et al, 2016;Fieblinger et al, 2018), or blood vessels (Lindgren et al, 2009;Ohlin et al, 2011;Booth et al, 2021). It remains unclear whether these cellular contributors cause macroscopic structural changes in the brain volume of LID.…”