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

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Samantha,Dinkins,Mai-Lynne,Kassai,Miki,Lyu,Shangru Meneely (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Restless Legs Syndrome (RLS) is often and successfully treated with dopamine receptoragonists that target the inhibitory D3 receptor subtype, however there is no clinicalevidence of a D3 receptor dysfunction in RLS patients. In contrast, genome-wideassociation studies in RLS patients have established that a mutation of the MEIS1 gene isassociated with an increased risk in developing RLS, but the effect of MEIS1 dysfunctionon sensorimotor function remain unknown. Mouse models for a dysfunctional D3receptor (D3KO) and Meis1 (Meis1KO) were developed independently, and each animalexpresses some features associated with RLS in the clinic, but they have not beencompared in their responsiveness to treatment options used in the clinic. We here confirmthat D3KO and Meis1KO animals show increased locomotor activities, but that onlyD3KO show an increased sensory excitability to thermal stimuli. Next we comparedthe effects of dopaminergics and opioids in both animal models, and we assessed D1and D3 dopamine receptor expression in the spinal cord, the gateway for sensorimotorprocessing. We found that Meis1KO share most of the tested behavioral properties withtheir wild type (WT) controls, including the modulation of the thermal pain withdrawalreflex 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 testedwith D1 receptor (D1R) agonists and antagonists. Subsequent Western blot analyses ofD1R and D3R protein expression in the spinal cord revealed a significant increase in D1Rbut not D3R expression in Meis1KO and D3KO over WT controls. As the D3R is mostlypresent 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, wespeculate that D3KO and Meis1KO represent two complementary animal models forRLS, in which the mechanisms of sensory (D3R-mediated) and motor (D1R-mediated)dysfunctions can be differentially explored.

Additional Information

Publication

Other

Language: English

Date: 2018

Keywords

RLS animal models, dopamine, D1 receptor, D3 receptor, Meis1, sensorimotor function, spinal cord

Email this document to