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Behavioral and cellular dopamine D₁ and D₃ receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.

ABSTRACT: Individually, D1 and D3 dopamine receptors (D₁R and D₃R, respectively) have been implicated in L-DOPA-induced dyskinesia (LID). Of late, direct D₁R-D₃R interactions have been linked to LID yet remain enigmatic. Therefore, the current research sought to characterize consequences of putative D₁R-D₃R interactions in dyskinesia expression and in LID-associated downstream cellular signaling. To do so, adult male Sprague-Dawley hemi-parkinsonian rats were given daily L-DOPA (6 mg/kg; s.c.) for 2 weeks to establish stable LID, as measured via the abnormal voluntary movements (AIMs) scale. Thereafter, rats underwent dose-response AIMs testing for the D₁R agonist SKF38393 (0, 0.3, 1.0, 3.0 mg/kg) and the D₃R agonist, PD128907 (0, 0.1, 0.3, 1.0 mg/kg). Each agonist dose-dependently induced dyskinesia, implicating individual receptor involvement. More importantly, when threshold doses were co-administered, rats displayed synergistic exacerbation of dyskinesia. Interestingly, this observation was not mirrored in general locomotor behaviors, highlighting a potentially dyskinesia-specific effect. To illuminate the mechanisms by which D₁R-D₃R co-stimulation led to in vivo synergy, levels of striatal phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) were quantified after administration of SKF38393 and/or PD128907. Combined agonist treatment synergistically drove striatal pERK1/2 expression. Together, these results support the presence of a functional, synergistic interaction between D₁R and D₃R that manifests both behaviorally and biochemically to drive dyskinesia in hemi-parkinsonian rats.

SUBMITTER: Lanza K

PROVIDER: S-EPMC9380415 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Behavioral and cellular dopamine D1 and D3 receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.

Lanza Kathryn K Meadows Samantha M SM Chambers Nicole E NE Nuss Emily E Deak Molly M MM Ferré Sergi S Bishop Christopher C

Neuropharmacology 20180621

Individually, D1 and D3 dopamine receptors (D1R and D3R, respectively) have been implicated in L-DOPA-induced dyskinesia (LID). Of late, direct D1R-D3R interactions have been linked to LID yet remain enigmatic. Therefore, the current research sought to characterize consequences of putative D1R-D3R interactions in dyskinesia expression and in LID-associated downstream cellular signaling. To do so, adult male Sprague-Dawley hemi-par ...[more]

PMID: 29936243

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Project description:The striatum is the main structure of the basal ganglia. The striatum receives inputs from various cortical areas, and its subregions play distinct roles in motor and emotional functions. Recently, striatal maps based on corticostriatal connectivity and striosome-matrix compartmentalization were developed, and we were able to subdivide the striatum into seven subregions. Dopaminergic modulation of the excitability of medium spiny neurons (MSNs) is critical for striatal function. In this study, we investigated the functional properties of dopamine signaling in seven subregions of the striatum from male mice. By monitoring the phosphorylation of PKA substrates including DARPP-32 in mouse striatal slices, we identified two subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Low D1 receptor signaling in the two subregions was maintained by phosphodiesterase (PDE)10A and muscarinic M4 receptors. In an animal model of 6-hydroxydopamine (6-OHDA)-induced hemi-parkinsonism, D1 receptor signaling was upregulated in almost all subregions including the DL-IR, but not in the IC. When L-DOPA-induced dyskinesia (LID) was developed, D1 receptor signaling in the IC was upregulated and correlated with the severity of LID. Our results suggest that the function of the striatum is maintained through the subregion-specific regulation of dopamine D1 receptor signaling and that the aberrant activation of D1 receptor signaling in the IC is involved in LID. Future studies focusing on D1 receptor signaling in the IC of the striatum will facilitate the development of novel therapeutics for LID.SIGNIFICANCE STATEMENT Recent progress in striatal mapping based on corticostriatal connectivity and striosome-matrix compartmentalization allowed us to subdivide the striatum into seven subregions. Analyses of D1 receptor signaling in the seven subregions identified two unique subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Aberrant activation of D1 receptor signaling in the IC is involved in L-DOPA-induced dyskinesia (LID). Previous studies of LID have mainly focused on the DL-IR, but not on the IC of the striatum. Future studies to clarify aberrant D1 receptor signaling in the IC are required to develop novel therapeutics for LID.

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Behavioral and cellular dopamine D₁ and D₃ receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.

Publications

Behavioral and cellular dopamine D<sub>1</sub> and D<sub>3</sub> receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.

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Dataset Information

Behavioral and cellular dopamine D1 and D3 receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.

Publications

Behavioral and cellular dopamine D&lt;sub&gt;1&lt;/sub&gt; and D&lt;sub&gt;3&lt;/sub&gt; receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Behavioral and cellular dopamine D₁ and D₃ receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.

Behavioral and cellular dopamine D<sub>1</sub> and D<sub>3</sub> receptor-mediated synergy: Implications for L-DOPA-induced dyskinesia.