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The Journal of Neuroscience, December 15, 2004, 24(50):11337-11345; doi:10.1523/JNEUROSCI.3698-04.2004

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Behavioral/Systems/Cognitive
Conversion of the Modulatory Actions of Dopamine on Spinal Reflexes from Depression to Facilitation in D₃ Receptor Knock-Out Mice

Stefan Clemens and Shawn Hochman

Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322

Descending monoaminergic systems modulate spinal cord function, yet spinal dopaminergic actions are poorly understood. Using the in vitro lumbar 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 D₃ receptor agonists pergolide and PD 128907 reduced MSR amplitude in WT but not D₃KO mice. Conversely, D₃ receptor 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 µM dopamine 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 D₃ receptors to limit reflex excitability. Moreover, in D₃ ligand-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 D₃ agonists, and likely involve increased reflex excitability, the D₃KO mouse putatively explains how impaired D₃ activity could contribute to this sleep disorder.

Key words: spinal cord reflex; monoamine; neuromodulation; restless legs syndrome; monosynaptic; mouse model

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Received Sep 7, 2004; revised November 2, 2004; accepted November 6, 2004.

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