Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA.
Veterans Administration Greater Los Angeles HealthCare System (VAGLAHS), Sepulveda, Los Angeles, CA.
Sleep. 2020 Feb 13;43(2). doi: 10.1093/sleep/zsz223.
Restless legs syndrome (RLS) has been hypothesized to be generated by abnormal striatal dopamine transmission. Dopaminergic drugs are effective for the treatment of RLS. However, long-term use of dopaminergic drugs causes adverse effects. We used iron-deficient (ID) and iron-replacement (IR) rats to address the neuropathology of RLS and to determine if a histamine H3 receptor (H3R) antagonist might be a useful treatment. Histamine H3R antagonists have been shown to decrease motor activity.
Control and ID rats were surgically implanted with electrodes for polysomnographic recording. After 3 days of baseline polysomnographic recordings, rats were systemically injected with the H3R agonist, α-methylhistamine, and antagonist, thioperamide. Recordings were continued after drug injection. Striatal H3R levels from control, ID, and IR rats were determined by western blots. Blood from control, ID, and IR rats was collected for the measurement of hematocrit levels.
α-Methylhistamine and thioperamide increased and decreased motor activity, respectively, in control rats. In ID rats, α-methylhistamine had no effect on motor activity, whereas thioperamide decreased periodic leg movement (PLM) in sleep. Sleep-wake states were not significantly altered under any conditions. Striatal H3R levels were highest in ID rats, moderate to low in IR rats, and lowest in control rats. Striatal H3R levels were also found to positively and negatively correlate with PLM in sleep and hematocrit levels, respectively.
A striatal histamine mechanism may be involved in ID anemia-induced RLS. Histamine H3R antagonists may be useful for the treatment of RLS.
不宁腿综合征（RLS）被认为是由纹状体多巴胺传递异常引起的。多巴胺能药物对 RLS 的治疗有效。然而，长期使用多巴胺能药物会引起不良反应。我们使用缺铁（ID）和铁替代（IR）大鼠来解决 RLS 的神经病理学问题，并确定组胺 H3 受体（H3R）拮抗剂是否是一种有用的治疗方法。组胺 H3R 拮抗剂已被证明可以减少运动活动。
对照和 ID 大鼠接受了用于多导睡眠描记术记录的电极手术植入。在 3 天的基线多导睡眠描记术记录后，大鼠系统地注射了 H3R 激动剂α-甲基组氨酸和拮抗剂噻哌酰胺。在药物注射后继续进行记录。通过 Western blot 确定对照、ID 和 IR 大鼠的纹状体 H3R 水平。从对照、ID 和 IR 大鼠采集血液以测量血细胞比容水平。
α-甲基组氨酸和噻哌酰胺分别增加和减少对照大鼠的运动活动。在 ID 大鼠中，α-甲基组氨酸对运动活动没有影响，而噻哌酰胺在睡眠中减少周期性腿部运动（PLM）。在任何情况下，睡眠-觉醒状态都没有明显改变。纹状体 H3R 水平在 ID 大鼠中最高，在 IR 大鼠中为中低，在对照大鼠中最低。还发现纹状体 H3R 水平与睡眠中的 PLM 和血细胞比容水平呈正相关和负相关。
纹状体组胺机制可能参与 ID 贫血引起的 RLS。组胺 H3R 拮抗剂可能对 RLS 的治疗有用。
