Clemens Stefan, Hochman Shawn
Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci. 2004 Dec 15;24(50):11337-45. doi: 10.1523/JNEUROSCI.3698-04.2004.
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 microM) decreased the monosynaptic "stretch" reflex (MSR) amplitude in WT animals and increased it in D3KO animals. Higher dopamine concentrations (10-100 microM) 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 microM) also depressed longer-latency (presumably polysynaptic) reflexes in WT but facilitated responses in D3KO mice. Additionally, in some experiments (e.g., during 10 microM 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.
下行单胺能系统调节脊髓功能，但脊髓多巴胺能作用却知之甚少。我们利用体外腰段脊髓，研究了多巴胺和D2样受体配体对野生型（WT）和D3受体敲除小鼠（D3KO）脊髓反射的影响。低多巴胺水平（1微摩尔）降低了WT动物的单突触“牵张”反射（MSR）幅度，而在D3KO动物中则增加了该幅度。较高的多巴胺浓度（10 - 100微摩尔）降低了两组的MSR幅度，但在WT中总是更强烈。与低多巴胺一样，D3受体激动剂培高利特和PD 128907降低了WT小鼠的MSR幅度，但对D3KO小鼠没有影响。相反，D3受体拮抗剂（GR 103691和萘法朵曲）增加了WT小鼠的MSR，但对D3KO小鼠没有作用。相比之下，更倾向于D2的激动剂溴隐亭和喹吡罗抑制了两组的MSR。低多巴胺（1 - 5微摩尔）也抑制了WT小鼠中潜伏期更长（可能是多突触的）反射，但促进了D3KO小鼠的反应。此外，在一些实验中（例如，WT小鼠在10微摩尔多巴胺或培高利特作用期间），多突触反射在MSR抑制的同时得到促进，表明对这些反射回路有不同的调节控制。因此，低多巴胺激活D3受体以限制反射兴奋性。此外，在对D3配体不敏感的小鼠中，兴奋性作用被揭示出来，在功能上将多巴胺的调节作用从抑制转变为促进。不宁腿综合征（RLS）是一种涉及肢体异常感觉的中枢神经系统疾病。由于RLS症状在夜间多巴胺水平最低时达到峰值，可被D3激动剂缓解，并且可能涉及反射兴奋性增加，D3KO小鼠推测可以解释D3活性受损如何导致这种睡眠障碍。
