Michael Williams Lab
The Williams Lab in the Division of Neurology at Cincinnati Children's Research Foundation has several different areas of focus to its research.
| Contact Dr. Williams |
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Michael T. Williams, PhD
Research Assistant Professor of Pediatrics
Children's Hospital Research Foundation
Child Neurology, MLC 7044
3333 Burnet Ave.
Cincinnati, OH 45229-3039
Phone 513-636-8624
Fax 513-636-3912 |
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The primary focus of the lab is on the effects of developmental exposure to various drugs of abuse, especially the substituted-amphetamines as well as the stress response of the animal following drug administration. In particular, we examine methamphetamine (MA) and methylenedioxymethamphetamine (MDMA), two compounds that are highly abused but there is little understanding about the consequences of fetal exposure.
We use the neonatal rat as a model of human third trimester exposure and have found that MA and MDMA produce long-term spatial learning deficits but that only MDMA produces deficits in path integration. Spatial learning is assessed using the Morris water maze and path integration using the Cincinnati water maze. The differences and commonalities in the learning deficits produced by these two drugs is of interest, especially since it may clarify the neurochemical, neuroendocrine, and/or molecular changes that underlie the different learning deficits produced by the drugs.
In pursuit of these issues, we have shown that neonatal rats exposed to MA or MDMA do not show an adult-like response to either drug; that is, no long-lasting alterations to neurotransmitters or any indication of neurotoxicity occur. We have also demonstrated that both MA and MDMA administration cause elevated corticosterone (CORT) and ACTH levels, although MA produces an extremely protracted increase (i.e., over 36 h after administration). Therefore, we are trying to understand and test the hypothesis that this protracted change may be altering the developing central nervous system and consequently alter learning and memory.
We also are beginning experiments examining the effects of another drug of abuse called 5-methoxy-diisopropyltryptamine or Foxy. This drug is fairly new in relation to MDMA and MA, however it has become such a problem that the DEA has classified the drug as Schedule I.
The second area of research is on the adult effects of these various drugs of abuse. While human populations show altered cognitive function following drug use, very few cognitive effects have been noted after adult exposure, although some of these drugs produce neurotoxicity. We are therefore investigating the exposure of animals to various dosing regimens and examining the learning potential of the animals following these administrations.
In conjunction with the learning studies, we are also investigating the underlying mechanisms involved in the drug-induced changes. In particular, we have been examining energy metabolism in these animals. One of our collaborators, Dr. Katie Holland, will be investigating the EEG response of adult animals following drug administration. In the near future we hope to be doing magnetic resonance spectroscopy on the animals using the new 7T magnet in the Imaging Research Center.
The lab has several collaborators with whom we are phenotyping various mutant mice. Various gene targeted knock-out mice are currently being examined and these include mice with altered genes for: PDE1B, NPAS3, MPS1, prosaposin, ubiquitous creatine kinase, brain-specific creatine kinase, and the alpha isoforms of the Na+/K+ ATPase.
We are also currently working on knocking out the creatine transporter since this gene deletion and/or mutation in humans leads to mental retardation. Future studies may include investigation of anti-epileptic drugs administered during the neonatal period.
Recent Publications
Williams MT, Schaefer TL, Ehrman LA, Able JA, Gudelsky GA, Sah R., Vorhees CV (2005). 3,4-Methylenedioxymethamphetamine administration on postnatal day 11 in rat increases pituitary-adrenal output and reduces striatal and hippocampal serotonin without altering SERT activity. Brain Research 1039(1/2):95-105.
Vorhees CV, Reed TM, Morford LL, Fukumura M, Wood SL, Brown CA, Skelton MR, McCrea AE, Rock SL, Williams MT (2005). Periadolescent rats (P41-50) exhibit increased susceptibility to d-methamphetamine-induced long-term spatial and sequential learning deficits compared to juvenile (P21-30 or P31-40) or adult rats (P51-60). Neurotoxicology and Teratology 27(1): 117-134.
Kuan CY, Schloemer AJ, Lu A, Burns KA, Weng WL, Williams MT, Strauss KI, Vorhees CV, Flavell RA, Davis RJ, Sharp FR, Rakic P (2004). Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. Journal of Neuroscience 24(47):10763-10772.
Skelton MR, Blankemeyer TL, Gudelsky GA, Brown-Strittholt CA, Vorhees CV, Williams MT (2004). Metyrapone attenuates the sequential learning deficits, but not monoamine depletions following d,l-fenfluramine administration to adult rats. Synapse 54(4): 214-222.
Williams MT, Brown CA, Skelton MR, Vinks AA, Vorhees CV (2004). Absorption and clearance of ±3,4-methylenedioxymethamphetamine from the plasma of neonatal rats. Neurotoxicology and Teratology 26(6): 849-856.
Vorhees CV, Reed TM, Skelton MR, and Williams MT (2004). Exposure to 3,4-methylenedioxymethamphetamine (MDMA) on postnatal days 11-20 induces reference but not working memory deficits in the Morris water maze in rats: implications of prior learning. International Journal of Developmental Neuroscience. 22(5/6): 247-259.
Williams MT, Moran MS, Vorhees CV. (2004). Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats. International Journal of Developmental Neuroscience. 22(5/6): 273-283.
Brown RW, Flanigan TJ, Thompson KN, Thacker SK, Schaefer TL, Williams MT (2004). Neonatal quinpirole treatment impairs Morris water task performance in early postweanling rats: Relationship to increases in corticosterone and decreases in neurotrophic factors Biological Psychiatry 56(3):161-168.
Williams MT, Brown RW, Vorhees CV (2004). Neonatal methamphetamine administration induces region-specific long-term neuronal morphological changes in the rat hippocampus, nucleus accumbens, and parietal cortex. European Journal of Neuroscience 19(12): 3165-3170.
Brown RW, Thompson KD, Thompson KN, Ward JJ, Thacker SK, Williams MT, and Kostrzewa RM. (2004). Adulthood nicotine treatment alleviates behavioral impairments in rats neonatally treated with quinpirole: Possible roles of acetylcholine function and neurotrophic factor expression. European Journal of Neuroscience 19(6): 1634-1642.
Williams MT, Blankemeyer TL, Schaefer TL, Brown CA, Gudelsky GA, Vorhees CV (2003). Long-term effects of neonatal methamphetamine exposure in rats on spatial learning in the Barnes maze and on cliff avoidance, corticosterone release, and neurotoxicity in adulthood. Dev Brain Res 147(1-2): 163-175.
Williams MT, Moran MS, Vorhees,CV. (2003) Refining the critical period for methamphetamine-induced spatial deficits in the Morris water maze. Psychopharmacology 168, 329-338.
Williams MT, Morford LL, Wood SL, Wallace TL, Fukumura M, Broening HW, Vorhees CV (2003). Developmental d-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory. Synapse 48, 138-148.
Crawford CA, Williams MT, Newman, E. R., McDougall SA, Vorhees CV (2003) Early postnatal methamphetamine exposure causes prolonged changes in dorsal striatal protein kinase A activity, dopamine D2-like binding sites, and dopamine content. Synapse 48, 131-137.
Williams MT, Morford LL, Wood SL, Rock SL, McCrea AE, Fukumura, M., Wallace TL, Broening HW, Moran MS, Vorhees CV (2003). Developmental 3,4-methylenedioxymethamphetamine (MDMA)-induced learning deficits are not related to undernutrition or litter effects: novel use of litter size to control for MDMA-induced growth decrements. Brain Research 968 (1), 89-101.
