Restless legs syndrome (RLS) and periodic leg movement (PLM) disorder, which produce one of the most profound variants of insomnia, affect 10% of the population and 32% of iron deficient (ID) anemia patients. Though dopaminergic drugs are effective in the treatment of RLS and PLM disorder, they are frequently only effective for short-term use. Augmentation of symptoms is often seen with long-term use. An animal model would greatly increase our understanding of RLS and PLM disorder, as has been the case for other disorders. Iron deficiency, which produces changes in dopaminergic neurons and receptors in the substantia nigra (SN) and putamen, has been reported to correlate with RLS. We hypothesize that GABAergic mechanisms in the SN may also play a critical role in the control of sleep and motor activity. We recently developed several animal models that exhibit sleep disorders similar to those seen in RLS patients. We found that neurotoxic NMDA lesions of the lateral ventral midbrain including the SN pars reticulata (SNR) produce hyposomnia with an increase in motor activity in slow wave sleep (SWS) in the cat. Our preliminary studies have shown that GABA levels in the SNR are positively correlated with wake time in the rat. We also found in our preliminary studies that muscimol, a GABAA receptor agonist, infused into the SNR decreases sleep and induces PLM in quiet wakefulness and SWS in the rat. Our preliminary study showed that rats with neurotoxic lesions of the putamen, which projects to the SNR via the globus pallidus, also exhibit hyposomnia and PLM in quiet wake and in sleep. In addition, our preliminary data showed that ID rats have insomnia and severe PLM in wake and in SWS. The sleep pattern and symptoms of putamen-lesioned rats and ID rats resemble human RLS patients. Our preliminary data showed that systemic injection of dopamine agonist suppresses PLM in putamen-lesioned and ID rats, similar to humans. These indicate that both putamen-lesioned and ID rats would serve as ideal animal models of primary and secondary RLS. We found that the sleep disturbances in ID rats can be improved by iron replacement (IR). We also found in our preliminary study that histamine H3 receptor (H3R) mechanisms play a role in the control of sleep-related motor activity. Systemic administration of a H3R antagonist effectively suppressed PLM in wake and in sleep, in both putamen-lesioned and ID rats. We found in our preliminary study that striatal levels of H3R are high in ID and low in normal and IR animals. We propose to determine the role that GABAergic and histaminergic mechanisms play in the regulation of sleep and motor activity, through the use of neurotoxic lesion, in vivo microdialysis HPLC analysis, microinfusion of GABAA receptor agonists and antagonists, systemic injection of H3R agonist and antagonist, Western blotting, and EEG spectral analysis techniques.

Public Health Relevance

Our discovery that the lateral substantia nigra pars reticulata plays a role in periodic leg movements in sleep may explain the link between sleep related motor disorders and Parkinsonism. The goal of the present project is to develop rat models of sleep related motor disorders, to determine the neural circuitry and neurotransmitters which underlie these disorders, and to test potential drugs for the treatment of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Gwinn, Katrina
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Sepulveda Research Corporation
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Lai, Yuan-Yang; Cheng, Yu-Hsuan; Hsieh, Kung-Chiao et al. (2018) Reply: The iron-deficient rat as a model of restless legs syndrome: Was anything lost in translation? Mov Disord 33:182-183
Lai, Yuan-Yang; Cheng, Yu-Hsuan; Hsieh, Kung-Chiao et al. (2017) Motor hyperactivity of the iron-deficient rat - an animal model of restless legs syndrome. Mov Disord 32:1687-1693