Keith J Lookingland, Ph.D.
Pharmacology & Toxicology
Dr. Keith J. Lookingland
B432 Life Sciences
1355 Bogue Street
East Lansing, MI 48823
Fields of Interest: The goal of research in my laboratory is to develop a murine model for periodic limb movements employing neurotoxin-induced lesions of the A11 diencephalospinal dopamine neurons and remote sensing assessment of hindlimb during the awake/sleep cycle.
- 1969-71 - Mathematics, Essex Community College, Baltimore, MD
- 1971-75 - B.S., Biology, Towson State College-Baltimore
- 1975-77 - M.S. Candidate, Biology, Towson State University-Baltimore
- 1977-82 - Ph.D., Physiology, University of Maryland-Baltimore
- 1982-87 - Research Associate, Pharmacology & Toxicology, Michigan State University
- 1987-92 - Assistant Professor, Pharmacology & Toxicology, Michigan State University
- 1992-present - Associate Professor, Pharmacology & Toxicology, Michigan State University
- 2006-10 - Director, Ph.D. Program, Pharmacology & Toxicology, Michigan State University
Restless Leg 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 PLM 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 PLM employing neurotoxin-induced lesions of the A11 diencephalospinal DA neurons and remote sensing assessment of hindlimb 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 "PLM-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, 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 neurotoxin-based model has several advantages over existing models for PLM 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.
Selected Achievements since 2001
- President, Michigan Chapter of the Society for Neuroscience, 2001-2003
- Treasurer, Michigan Chapter of the Society for Neuroscience, 1996-2001
- Michigan State University, Neuroscience Program, Faculty Award (2010)
- College of Osteopathic Medicine, Michigan State University – Outstanding Curricular Contributions Award, 2004
- College of Osteopathic Medicine, Curriculum Committee (Chair – 2007-09; Vice Chair – 2009-10)
- Director - Pharmacology & Toxicology Doctoral Graduate Program (2006-2010)
- Benskey M, Lee KY, Parikh K, Lookingland KJ, Goudreau JL. Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein. Neurotoxicology. 2013 Jul;37:144-53. doi: 10.1016/j.neuro.2013.04.002. Epub 2013 May 1. PubMed PMID: 23643664.
- Tiernan CT, Edwin EA, Goudreau JL, Atchison WD, Lookingland KJ. The role of de novo catecholamine synthesis in mediating methylmercury-induced vesicular dopamine release from rat pheochromocytoma (PC12) cells. Toxicol Sci. 2013 May;133(1):125-32. doi: 10.1093/toxsci/kft025. Epub 2013 Feb 19. PubMed PMID: 23425605; PubMed Central PMCID: PMC3627552.
- Simkins TJ, Janis KL, McClure AK, Behrouz B, Pappas SS, Lehner A, Kaminski NE, Goudreau JL, Lookingland KJ, Kaplan BL. Comparison of the D2 receptor regulation and neurotoxicant susceptibility of nigrostriatal dopamine neurons in wild-type and CB1/CB2 receptor knockout mice. J Neuroimmune Pharmacol. 2012 Sep;7(3):533-8. doi: 10.1007/s11481-012-9375-y. Epub 2012 May 27. PubMed PMID: 22639229; PubMed Central PMCID: PMC3479639.
- Benskey M, Behrouz B, Sunryd J, Pappas SS, Baek SH, Huebner M, Lookingland KJ, Goudreau JL. Recovery of hypothalamic tuberoinfundibular dopamine neurons from acute toxicant exposure is dependent upon protein synthesis and associated with an increase in parkin and ubiquitin carboxy-terminal hydrolase-L1 expression. Neurotoxicology. 2012 Jun;33(3):321-31. doi: 10.1016/j.neuro.2012.02.001. Epub 2012 Feb 9. Erratum in: Neurotoxicology. 2012 Jun;33(3):406. PubMed PMID: 22342763; PubMed Central PMCID: PMC3363356.
- Pappas SS, Kennedy T, Goudreau JL, Lookingland KJ. Opioid-mediated regulation of A11 diencephalospinal dopamine neurons: pharmacological evidence of activation by morphine. Neuropharmacology. 2011 Sep;61(4):614-21. doi: 10.1016/j.neuropharm.2011.05.002. Epub 2011 May 13. PubMed PMID: 21605572; PubMed Central PMCID: PMC3130120.
Additional articles at PubMed