Dopamine D3 Receptor Plasticity in Parkinson's Disease and L-DOPA-Induced Dyskinesia

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.

Keywords: D1R–D3R; L-DOPA-induced dyskinesia; Parkinson’s Disease; dopamine D1 receptor; dopamine D3 receptor; striatum.

Figure 1

Summary of major changes associated with dopamine D1/D3 receptors in the striatum and nigra. Studies in cells, mice, rats, non-human primates and humans have demonstrated dynamic changes to dopamine receptors D1 (D1R) and D3 (D3R) across Parkinson’s Disease (PD) and L-DOPA-induced dyskinesia (LID). In the denervated state, D1R are sensitized. This is partially achieved by increases in membrane-bound G-protein-coupled D1R. In L-DOPA-induced dyskinesia (LID), D1R are unable to internalize and effectively terminate signaling, leading to further supersensitization and second messenger signaling. Some evidence suggests that striatal D3R are also supersensitive in PD but are expressed at almost undetectable levels. In LID, D3R are upregulated predominantly on D1R cells, where they display cooperativity with D1R at the level of downstream signaling. In contrast, in striatonigral terminals, D3R inhibits D1R signaling in the denervated state. This inhibitory property is maintained in severely (but not mildly) dyskinetic subjects. Image credit: Servier medical art (http://smart.servier.com/; Access date: 15 March 2021).

Figure 2

Theoretical signaling pathways of the dopamine D1/D3 receptors in the healthy, Parkinsonian or dyskinetic striatum. In the intact brain, dopamine (DA) is released from striatonigral terminals and interacts with post-synaptic D1 receptors (D1R; low DA affinity but high expression) and dopamine D3 receptors (D3R; high DA affinity but low expression) which couple with canonical G-proteins to increase or decrease G-protein signaling, respectively. Each of these receptor properties is theoretically maintained in PD, with reductions in DA levels due to the retraction of striatonigral terminals. D1R is sensitized due to increased presence at the membrane. In the dyskinetic state, DA is exogenously provided via L-DOPA. D3R is upregulated and interacts with D1R, potentially in the form of a heteromer. D1R–D3R cooperate to drive downstream signaling, such as phosphorylation of ERK (pERK). This signaling might be G-protein-independent. cAMP: cyclic AMP; AC: adenylyl cyclase. Image credit: Servier medical art (http://smart.servier.com/; Access date: 15 March 2021).