Neurones in the median preoptic nucleus (MnPN) and the ventrolateral preoptic area (vlPOA) express immunoreactivity for c-Fos protein following sustained sleep, and display elevated discharge rates during both non-REM and REM sleep compared to waking. We evaluated the hypothesis that MnPN and vlPOA sleep-active neurones are GABAergic by combining staining for c-Fos protein with staining for glutamic acid decarboxylase (GAD). In a group of six rats exhibiting spontaneous total sleep times averaging 82.2 ± 5.1% of the 2 h immediately prior to death, >75% of MnPN neurones that were Fos-immunoreactive (IR) were also GAD-IR. Similar results were obtained in the vlPOA. In a group of 11 rats exhibiting spontaneous sleep times ranging from 20 to 92%, the number of Fos + GAD-IR neurones in MnPN and vlPOA was positively correlated with total sleep time. Compared to control animals, Fos + GAD-IR cell counts in the MnPN were significantly elevated in rats that were sleep deprived for 24 h and permitted 2 h of recovery sleep. These findings demonstrate that a majority of MnPN and vlPOA neurones that express Fos-IR during sustained spontaneous sleep are GABAergic. They also demonstrate that sleep deprivation is associated with increased activation of GABAergic neurones in the MnPN and vlPOA.

Background Abnormal striatal dopamine transmission has been hypothesized to cause the restless legs syndrome. Dopaminergic drugs are commonly used to treat restless legs syndrome. However, they cause adverse effects with long term use. An animal model would allow the systematic testing of potential therapeutic drugs. Objectives A high prevalence of restless legs syndrome was reported in iron deficient anemic patients. We hypothesized that the iron deficient animal exhibits signs similar to those in restless legs syndrome patients. Methods After baseline polysomnographic recordings iron deficient rats received pramipexole injection. Then, iron deficient rats were fed a standard rodent diet and polysomnographic recording were performed for 2 days each week for 4 weeks. Results Iron deficient rats have low hematocrit levels and show signs of restless legs syndrome: sleep fragmentation and periodic leg movements in wake and in slow wave sleep. Iron deficient rats had a positive response to pramipexole treatment. After the iron deficient rats were fed the standard rodent diet, hematocrit returned to normal levels, sleep quality improved, with increased average duration of wake and slow wave sleep episodes. Periodic leg movements decreased during both waking and sleep. Hematocrit levels positively correlated with the average duration of episodes in wake and in slow wave sleep, and negatively correlated with periodic leg movements in wake and in sleep. Western blot analysis showed that striatal dopamine transporter levels were higher in iron deficient rats. Conclusions The iron deficient rat is a useful animal model of iron deficient anemic restless legs syndrome.

Study Objectives 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. Methods 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. Results 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. Conclusions A striatal histamine mechanism may be involved in ID anemia-induced RLS. Histamine H3R antagonists may be useful for the treatment of RLS.

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