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

ABSTRACT

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 Ca2+ 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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.