Keith J. Lookingland, PhD
- Faculty, Training Faculty, Cellular & Molecular
Associate Professor, Pharmacology & Toxicology
Ph.D., 1982, University of Maryland
Restless Legs Syndrome (RLS) is a common disorder characterized by a compelling urge to move the legs and unpleasant sensations of the extremities that occur during rest or sleep. RLS prevalence is higher in females as compared with males, and prevalence increases with age suggesting a neurodegenerative etiology for RLS. Most RLS patients display circadian periodic limb movements (PLM), which (like RLS) are more prevalent in women than men and increase with age. The pathogenesis of RLS is likely to involve loss of dopamine (DA) inhibitory control of spinal sensorimotor networks via an action at D2/3 receptors.
The goal of research in my laboratory is to develop a murine model for RLS employing neurotoxin-induced lesions of the A11 diencephalic-spinal DA neurons and remote sensing assessment of PLM during the awake/sleep cycle. The underlying hypothesis is that selective destruction of A11 DA neurons terminating in the lumbar spinal cord will cause deficits in inhibitory regulation of hindlimb movements consistent with those exhibited in RLS, and that treatment with a D2/3 agonist should reverse "RLS-like" behaviors in neurotoxin-lesioned mice. Our laboratory employs retrograde tract tracing, dual-label immunohistochemistry, stereology and neurochemistry to determine the location and distribution of A11 DA neurons projecting to the lumbar spinal cord in male and female mice, and determine if there are gonadal hormone-dependent circadian rhythms or if changes in iron status alter the activity of these neurons. The effects of selective, neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) induced lesions of A11 DA neurons on DA levels in the lumbar spinal cord, and open field activity, PLM (measured by remote sensor EMG) and sleep (measured by remote sensor EEG) are also studied in my laboratory, as well as the influence of iron status and gonadal hormones on susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and MPP+ neurotoxicity, and the ability of a D2/3 agonist (ropinirole) to reverse behavioral changes in MPP+ lesioned male and female mice. This model has several advantages over existing models for RLS and may be employed in the development of novel treatments for RLS as well as for elucidating the mechanisms underlying the untoward effects (i.e. augmentation, rebound) of current therapeutic agents.