Abstract
Parkinson’s Disease (PD) is characterized by primary and secondary plasticity that occurs in response to progressive degeneration and long-term L-DOPA treatment. Some of this plasticity contributes to the detrimental side effects associated with chronic L-DOPA treatment, namely L-DOPA-induced dyskinesia (LID). The dopamine D3 receptor (D3R) has emerged as a promising target in LID management as it is upregulated in LID. This upregulation occurs primarily in the D1-receptor-bearing (D1R) cells of the striatum, which have been repeatedly implicated in LID manifestation. D3R undergoes dynamic changes both in PD and in LID, making it difficult to delineate D3R’s specific contributions, but recent genetic and pharmacologic tools have helped to clarify its role in LID. The following review will discuss these changes, recent advances to better clarify D3R in both PD and LID and potential steps for translating these findings.
Highlights
Parkinson’s Disease (PD) is the second-most-common neurodegenerative disorder and is primarily characterized by the death of midbrain dopaminergic neurons in the substantia nigra pars compacta
This is due to the fact that nuclei within the basal ganglia undergo significant changes to compensate for the progressive loss of dopaminergic cells
We previously demonstrated that systemic coadministration of D1R and D3 Receptor (D3R) agonists results in synergistic increases in both dyskinesia and striatal expression of pERK1/2 [52], supporting previous research demonstrating the site-specific cooperativity of D1R–D3R in downstream signaling [41,77]
Summary
Parkinson’s Disease (PD) is the second-most-common neurodegenerative disorder and is primarily characterized by the death of midbrain dopaminergic neurons in the substantia nigra pars compacta. Behavioral manifestations of PD do not appear until significant cell death has already occurred [2]. This is due to the fact that nuclei within the basal ganglia undergo significant changes to compensate for the progressive loss of dopaminergic cells. Some of this compensation is clearly evidenced in morphological studies that show enlarged remaining nigrostriatal terminals, innervation of projections from non-dopaminergic areas and post-synaptic dendritic sprouting [3]. Over 60 years ago, L-DOPA was discovered as an effective treatment to replenish the loss of endogenous dopamine [4].
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