Long-term treatment with dopamine D3 receptor agonists induces a behavioral switch that can be rescued by blocking the dopamine D1 receptor

Dinkins, Mai-Lynne; Lallemand, Perrine; Clemens, Stefan

doi:10.1016/j.sleep.2017.10.001

Cited by 20 publications

(8 citation statements)

References 45 publications

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“…Dopamine receptors were recently discovered as key therapeutic targets involved in immunoregulation and the inflammatory response [ 41 ]. Previously reported active compounds were shown to mainly activate or inhibit dopamine receptors [ 42 , 43 ]; however, we found that isosibiricin did not directly activate DRD1/D2 but significantly upregulated the expression of DRD1/D2 mRNA, further promoting DRD1/D2-dependent inflammasome signalling pathway inactivation and blocking inflammatory mediator production. In addition, the level of cAMP was regulated by DRD1/D2, but we detected that isosibiricin did not affect the level of cAMP (Supplementary Fig.…”

Section: Discussioncontrasting

confidence: 62%

Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway

Wang

Cui

et al. 2019

Acta Pharmacol Sin

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Microglia-mediated neuroinflammation is a crucial risk factor for neurological disorders. Recently, dopamine receptors have been found to be involved in multiple immunopathological processes and considered as valuable therapeutic targets for inflammation-associated neurologic diseases. In this study we investigated the anti-neuroinflammation effect of isosibiricin, a natural coumarin compound isolated from medicinal plant Murraya exotica . We showed that isosibiricin (10−50 μM) dose-dependently inhibited lipopolysaccharide (LPS)-induced BV-2 microglia activation, evidenced by the decreased expression of inflammatory mediators, including nitrite oxide (NO), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and interleukin-18 (IL-18). By using transcriptomics coupled with bioinformatics analysis, we revealed that isosibiricin treatment mainly affect dopamine receptor signalling pathway. We further demonstrated that isosibiricin upregulated the expression of dopamine D1/2 receptors in LPS-treated BV-2 cells, resulting in inhibitory effect on nucleotide binding domain-like receptor protein 3 (NLRP3)/caspase-1 inflammasome pathway. Treatment with dopamine D1/2 receptor antagonists SCH 23390 (1 μM) or sultopride (1 μM) could reverse the inhibitory effects of isosibiricin on NLRP3 expression as well as the cleavages of caspase-1 and IL-1β. Collectively, this study demonstrates a promising therapeutic strategy for neuroinflammation by targeting dopamine D1/2 receptors.

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Section: Discussioncontrasting

confidence: 62%

Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway

Wang

Cui

et al. 2019

Acta Pharmacol Sin

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“…As recent findings from our lab point to a possible involvement of the D1 receptor in the face of D3 dysfunction (Brewer et al, 2014 ) or prolonged D3R agonist exposure (Dinkins et al, 2017 ), we next tested the effects of the D1 receptor agonist, SKF 38393 (SKF, Figure 5 ). We found that treatment with SKF had no significant effect in WT meis 1 animals (Ctrl: 99.9 ± 8.2%; SKF: 92 ± 6.4%, p = 0.77, paired t -test, n = 5, power: 0.05, Figure 5A1 ), while the same treatment led to significant decrease of withdrawal latencies in Meis1KO (Ctrl: 99.9 ± 8.2%; SKF: 82.4 ± 5.7%, p = 0.001, paired t -test, N = 7, power: 0.98, Figure 5A2 ).…”

Section: Resultsmentioning

confidence: 99%

“…We tested the effects of levodopa (L-DOPA, 10 mg/kg, Acros Organics, Geel, Belgium), the D3 receptor agonist, pramipexole (0.5 mg/kg, ApexBio Technology LLC, Houston, TX), the D3 receptor antagonist, SB277011-A (10 mg/kg, Abcam Cambridge, MA), the D1 agonist, SKF 38393 (10 mg/kg, Tocris, Ellisville, MO), the D1 receptor antagonist, SCH 39166 (5 mg/kg, Tocris, Ellisville, MO), and morphine (morphine sulfate salt pentahydrate, 2 mg/kg, Sigma-Aldrich St. Louis, MO). Drug concentrations were chosen based on previous publications by others and us (Acquas and Di Chiara, 1999 ; Williams et al, 2006 ; Brewer et al, 2014 ; Solís et al, 2015 ; Dinkins et al, 2017 )…”

Section: Methodsmentioning

confidence: 99%

Differential Dopamine D1 and D3 Receptor Modulation and Expression in the Spinal Cord of Two Mouse Models of Restless Legs Syndrome

Meneely

Dinkins

Kassai

et al. 2018

Front. Behav. Neurosci.

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Restless Legs Syndrome (RLS) is often and successfully treated with dopamine receptor agonists that target the inhibitory D3 receptor subtype, however there is no clinical evidence of a D3 receptor dysfunction in RLS patients. In contrast, genome-wide association studies in RLS patients have established that a mutation of the MEIS1 gene is associated with an increased risk in developing RLS, but the effect of MEIS1 dysfunction on sensorimotor function remain unknown. Mouse models for a dysfunctional D3 receptor (D3KO) and Meis1 (Meis1KO) were developed independently, and each animal expresses some features associated with RLS in the clinic, but they have not been compared in their responsiveness to treatment options used in the clinic. We here confirm that D3KO and Meis1KO animals show increased locomotor activities, but that only D3KO show an increased sensory excitability to thermal stimuli. Next we compared the effects of dopaminergics and opioids in both animal models, and we assessed D1 and D3 dopamine receptor expression in the spinal cord, the gateway for sensorimotor processing. We found that Meis1KO share most of the tested behavioral properties with their wild type (WT) controls, including the modulation of the thermal pain withdrawal reflex by morphine, L-DOPA and D3 receptor (D3R) agonists and antagonists. However, Meis1KO and D3KO were behaviorally more similar to each other than to WT when tested with D1 receptor (D1R) agonists and antagonists. Subsequent Western blot analyses of D1R and D3R protein expression in the spinal cord revealed a significant increase in D1R but not D3R expression in Meis1KO and D3KO over WT controls. As the D3R is mostly present in the dorsal spinal cord where it has been shown to modulate sensory pathways, while activation of the D1Rs can activate motoneurons in the ventral spinal cord, we speculate that D3KO and Meis1KO represent two complementary animal models for RLS, in which the mechanisms of sensory (D3R-mediated) and motor (D1R-mediated) dysfunctions can be differentially explored.

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“…A Hargreaves IITC Plantar Analgesia Meter (IITC Inc., Woodland Hills, CA) was used to assess thermal pain reflex withdrawal latencies as a function of the diets in a subset of animals as previously described ( 32 , 33 , 48 ). In short, animals were weighed and placed into the individual acrylic enclosures on top of an elevated glass platform.…”

Section: Methodsmentioning

confidence: 99%

Effects of iron-deficient diet on sleep onset and spinal reflexes in a rodent model of Restless Legs Syndrome

Woods,

Basco,

Clemens

2023

Front. Neurol.

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Restless Legs Syndrome (RLS) is a common sensorimotor and a sleep disorder that affects 2.5–10% of the European and North American populations. RLS is also often associated with periodic leg movements during sleep (PLMS). Despite ample evidence of genetic contributions, the underlying mechanisms that elicit the sensory and motor symptoms remain unidentified. Clinically, RLS has been correlated with an altered central iron metabolism, particularly in the brain. While several animal models have been developed to determine the outcome of an altered iron homeostasis on brain function, the potential role of an altered iron homeostasis on sleep and sensorimotor circuits has not yet been investigated. Here, we utilize a mouse model to assess the effects of an iron-deficient (ID) but non-anemic state on sleep time and episodes, and sensorimotor reflexes in male and female mice. We found that animals on the ID diet displayed an increased expression of the transferrin receptor in the spinal cord, confirming the results of previous studies that focused only on the impact of ID in the brain. We also demonstrate that the ID diet reduced hematocrit levels compared to controls but not into the anemic range, and that animals on the ID diet exhibited RLS-like symptoms with regard to sleep onset and spinal cord reflex excitability. Interestingly, the effects on the spinal cord were stronger in females than in males, and the ID diet-induced behaviors were rescued by the return of the animals to the control diet. Taken together, these results demonstrate that diet-induced ID changes to CNS function are both inducible and reversible, and that they mimic the sleep and sensorimotor RLS symptoms experienced in the clinic. We therefore propose replacing the commonly used phrase “brain iron deficiency” (BID) hypothesis in the RLS research field with the term “iron deficiency in the central nervous system” (ID-CNS), to include possible effects of altered iron levels on spinal cord function.

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Long-term treatment with dopamine D3 receptor agonists induces a behavioral switch that can be rescued by blocking the dopamine D1 receptor

Cited by 20 publications

References 45 publications

Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway

Isosibiricin inhibits microglial activation by targeting the dopamine D1/D2 receptor-dependent NLRP3/caspase-1 inflammasome pathway

Differential Dopamine D1 and D3 Receptor Modulation and Expression in the Spinal Cord of Two Mouse Models of Restless Legs Syndrome

Effects of iron-deficient diet on sleep onset and spinal reflexes in a rodent model of Restless Legs Syndrome

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