The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Abstract

The dopamine D5 receptor (D5R) is a Gα s-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, it affects up to 4% of people aged 65 years or more 1. Hallmarks of the disorder are motor symptoms such as tremor, rigidity, bradykinesia and gait disturbances 2 , which are a result of the selective degeneration of dopaminergic neurons within the substantia nigra pars compacta and thus not by but of dopamine depletion 3. Up to today, L-DOPA treatment remains the gold standard treatment for PD. In the majority of patients, the efficacy of L-DOPA is reduced and debilitating involuntary movements, termed L-DOPA-induced dyskinesia (LID), develop during chronic L-DOPA treatment over several years 4. Various pharmacological tools are currently investigated with the aim to mitigate these complications. The striatum is comprised mainly by two types of GABAergic projection neurons (SPNs) that are categorized based on their predominant expression of either D1-or D2 receptors, together making up over 95% of all striatal neurons 5. The spiny neurons that project directly to the basal ganglia output nuclei are termed 'direct pathway' or dSPNs and express D1 receptor (D1R), that signals via the G proteins Gα s /Gα olf to PKA and enhances cAMP production. The other class of projection neurons is termed 'indirect pathway' or iSPNs, and they express the inhibitory, Gα i/o-coupled D2 receptor (D2R) 6 , leading to less cAMP being produced. The balance between the two pathways is crucial for voluntary movement control and is disturbed in PD. In addition, cholinergic interneurons (CINs), which represent 1-3% of striatal neurons but are extensively arborized, gat...

Levodopa Causes Striatal Cholinergic Interneuron Burst‐Pause Activity in Parkinsonian Mice

“…Alternatively, the observed effects could be due to ligand‐independent D1/D5 receptor activity. The D5R has high constitutive activity, 36,37 and a recent study suggested that its expression is increased in striatal tissue from dyskinetic mice 38 . Because constitutive activity relates to levels of D5R expression and may result in a time‐dependent accumulation of intracellular cAMP, 37 we tested the effects of an inhibitor of the cAMP cascade, Rp‐cAMPS, on SCINs from dyskinetic mice (Fig.…”

Current Knowledge on the Background, Pathophysiology and Treatment of Levodopa-Induced Dyskinesia—Literature Review

“…Decreasing the striatal levels of Ras-guanine nucleotide-releasing factor (Ras-GFR1) leads to inhibition of the Ras/ERK pathway in parkinsonian mice. Ras-GFR1 affects the Ras-ERK pathway only in dSPNs, without affecting the cholinergic interneurons of ChIs [ 80 ]. It, therefore, affects specific downstream D1R pathways, consequently inhibiting the development of hypersensitivity to DA stimulation in the neurons.…”

“…It, therefore, affects specific downstream D1R pathways, consequently inhibiting the development of hypersensitivity to DA stimulation in the neurons. This is associated with LID developing less, although dopaminergic stimulation retains its therapeutic effect on parkinsonian motor symptoms [ 80 , 81 ].…”

Carnosic Acid Alleviates Levodopa-Induced Dyskinesia and Cell Death in 6-Hydroxydopamine-lesioned Rats and in SH-SY5Y Cells

“…The AIM scores from four subtypes were summed for each time point. The ALO score (sum of the axial, limb, and orofacial scores) is more responsive to human dyskinesia than are locomotive scores ( Castello et al, 2020 ). Therefore, the ALO score was also analyzed in this study.…”