Keith Lookingland, Associate Professor
1969-71 Essex Community College (Mathematics), Baltimore, MD
1971-75 B.S. (Biology), Towson State College, Baltimore, MD
1975-77 M.S. candidate (Biology), Towson State University, Baltimore, MD
1977-82 Ph.D. (Physiology), University of Maryland, Baltimore, MD
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 - present, Director, Pharmacology & Toxicology Graduate Program
Research Synopsis
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 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.
Current Projects
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 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.
Selected Achievements since 2001
Treasurer, Michigan Chapter of the Society for Neuroscience, 1996-2001
President, Michigan Chapter of the Society for Neuroscience, 2001-2003
Honors/Awards
College of Osteopathic Medicine, Michigan State University – Outstanding Curricular Contributions Award, 2004
Selected Samples of Publications Since 2001
Wang DH, Wu W, Lookingland KJ: Degeneration of capsaicin-sensitive sensory nerves leads to increased salt-sensitivity via enhancement of sympathoexcitatory response. Hypertension 37(2 Pt 2): 440-443, 2001.
McMahon CD, Radcliff RP, Lookingland KJ, Tucker HA: Neuroregulation of growth hormone secretion in domestic animals. Domestic Anim. Endocrinol. 20(2): 65-87, 2001.
McMahon CD, Chapin LT, Radcliff RP, Lookingland KJ, Tucker HA: Somatostatin inhibits a2-adrenoergic induced secretion of growth hormone-releasing hormone. Neuroendocrinology 73(3): 417-425, 2001.
McMahon CD, Chapin LT, Radcliff RP, Lookingland KJ, Tucker HA: GH-releasing peptide-6 overcomes refractoriness of somatotropes to GHRH after feeding. J. Endocrinol. 170(1): 235-241, 2001.
Radcliff RP, Lookingland KJ, Chapin LT, Tucker HA: Pituitary adenylate cyclase-activating polypeptide induces secretion of growth hormone in cattle. Domestic Anim. Endocrinol. 21: 187-196, 2001
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Radcliff RP, Lookingland KJ, McMahon CD, Chapin LT, Tucker HA: Thyrotropin releasing-hormone mediates serotonin-induced secretion of GH in cattle. Domestic Anim. Endocrinol. 24(2): 137-153, 2003.
Zheng JS, Yang XQ, Lookingland KJ, Fink GD, Hesslinger C, Kapatos G, Kovesdi I, Chen AF: Gene transfer of human guanosine 5’-triphosphate cyclohydrolase I restores vascular tetrahydrobiopterin level and endothelial function in mineralocorticoid hypertension. Circulation 108: R53-R60, 2003.
Schulz KM, Richardson HN, Romeo RD, Morris JA, Lookingland KJ, Sisk CL: Medial preoptic area dopaminergic responses to female pheromones develop during puberty in the male Syrian hamster. Brain Res. 988(1-2): 139-145, 2003.
Luo M, Fink GD, Lookingland KJ, Morris JA, Galligan JJ: Impaired function of a2-adrenergic autoreceptors on sympathetic nerves associated with mesenteric arteries and veins in DOCA-salt hypertension. Amer. J. Physiol. 286(4): H1558-H1564, 2004.
Ni W, Thompson J, Northcott CA, Lookingland KJ, Watts SW: The serotonin transporter is present and functional in peripheral arterial smooth muscle. J. Cardiovasc. Pharmacol. 43(6): 770-781, 2004.
Drolet RE, Behrouz B, Lookingland KJ, Goudreau JL: Mice lacking a-synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology 25(5): 761-769, 2004.
Lookingland KJ, Moore KE: Functional neuroanatomy of hypothalamic dopaminergic neuroendocrine systems. In “Handbook of Chemical Neuroanatomy,” Vol. 20, Chapter 8: 433-521, 2005.
Ni, W., C.S. Wilhelm, M. Bader, D.L. Murphy, K.J. Lookingland and S.W. Watts, 2005. (+)-Norfenflura-mine-induced arterial contraction is not dependent on endogenous 5-HT or 5-HTT. J. Pharmacol. Exp. Ther. 314(3): 953-960.
McCall, R.B., K.J. Lookingland, P.J. Bedard and R.M. Huff, 2005. Sumanirole, a highly dopamine D2-selective receptor agonist: In vitro and in vivo pharmacologic characterization and efficacy in animal models of Parkinson's disease. J. Pharmacol. Exp. Ther. 314(3): 1248-1256.
Drolet, R.E., B. Behrouz, K.J. Lookingland and J.L. Goudreau, 2006. Substrate-mediated enhancement of phosphorylated tyrosine hydroxyase in nigrostriatal dopamine neurons: Evidence for a role of alpha-synuclein. J. Neurochem. 96: 950-959.
Ni, W., K.J. Lookingland and S.W. Watts, 2006. Arterial 5-HT transporter function is impaired in DOCA and LNNA but not spontaneously hypertensive rats. Hypertension 48: 134-140.
Ni, W., K. Lookingland, S.W. Watts, 2006. Response to blood pressure in mutant rats lacking the 5-hydroxytryptamine transporter. Hypertension, E-Pub ahead of print, October 2, 2006.
Behrouz, B., R.E. Drolet, Z.A. Sayed, K.J. Lookingland, J.L. Goudreau, 2007, Unique responses to mitochondrial complex I inhibition in tuberoinfundibular dopamine neurons may impart resistance to toxic insult. Neuroscience 147: 592-598.
Pappas, S.S., B. Behrouz, K.L. Janis, J.L. Goudreau, K.J. Lookingland, 2008, Lack of D2 Receptor Mediated Regulation of Dopamine Synthesis in A11 Diencephalospinal Neurons in Male and Female Mice, Brain Res. 1214: 1-10.