Conversion of the Modulatory Actions of Dopamine on Spinal Reflexes from Depression to Facilitation in D3Receptor Knock-Out Mice

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Abstract
Descending monoaminergic systems modulate spinal cord function, yet spinal dopaminergic actions are poorly understood. Using thein vitrolumbar cord, we studied the effects of dopamine and D2-like receptor ligands on spinal reflexes in wild-type (WT) and D3-receptor knock-out mice (D3KO).Low dopamine levels (1 μm) decreased the monosynaptic “stretch” reflex (MSR) amplitude in WT animals and increased it in D3KO animals. Higher dopamine concentrations (10-100 μm) decreased MSR amplitudes in both groups, but always more strongly in WT. Like low dopamine, the D3receptor agonists pergolide and PD 128907 reduced MSR amplitude in WT but not D3KO mice. Conversely, D3receptor antagonists (GR 103691 and nafadotride) increased the MSR in WT but not in D3KO mice. In comparison, D2-preferring agonists bromocriptine and quinpirole depressed the MSR in both groups. Low dopamine (1-5 μm) also depressed longer-latency (presumably polysynaptic) reflexes in WT but facilitated responses in D3KO mice. Additionally, in some experiments (e.g., during 10 μmdopamine or pergolide in WT), polysynaptic reflexes were facilitated in parallel to MSR depression, demonstrating differential modulatory control of these reflex circuits. Thus, low dopamine activates D3receptors to limit reflex excitability. Moreover, in D3ligand-insensitive mice, excitatory actions are unmasked, functionally converting the modulatory action of dopamine from depression to facilitation.Restless legs syndrome (RLS) is a CNS disorder involving abnormal limb sensations. Because RLS symptoms peak at night when dopamine levels are lowest, are relieved by D3agonists, and likely involve increased reflex excitability, the D3KO mouse putatively explains how impaired D3activity could contribute to this sleep disorder.