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Health Science Campus
Block Health Science Building
Mail Stop # 1007
3000 Arlington Avenue
Toledo, Ohio 43614-2598
|Professor and Chairman|
Office: Block Health Sciences Building, Room 130B
Our primary research interests are in neuropharmacology, neurodegeneration, and the neurotoxicity of the amphetamines, in particular, methamphetamine (Speed) and MDMA (Ecstasy). The overall hypothesis is that the amphetamines, through the enhanced release of dopamine and glutamate, promote excitotoxicity, free-radical mediated oxidative stress, and produce a compromised bioenergetic state that damage dopamine and 5HT neurons. We have been continuously funded by the NIH since 1986.
The methodologies used in our lab range from environmental manipulations and measures
of behavior to cellular approaches such as in vivo microdialysis, cell culture, immunohistochemistry, protein biochemistry, and measures
of oxygen free radicals and oxidative stress.
Cellular mechanisms of MDMA and METH toxicity
Cultures of neurons are being used to examine the mechanisms mediating the toxic actions of the amphetamines. Measures of oxidative stress using traditional and novel assays, cell morphology, mitochondrial function and transporter protein trafficking are being examined. We are also examining the effects of dopamine formation in serotonin neurons and the role of abnormal protein degradation in causing cell death.
METH and MDMA toxicity – role of glutamate, oxidative stress, and neuroinflammation
We have a long-standing interest in the mechanisms mediating the toxicity of the widely abused psychostimulant drugs, methamphetamine and MDMA. Methamphetamine (METH) and MDMA damage dopamine and/or serotonin nerve terminals but the exact mechanisms leading to this damage are unknown. We are evaluating the causes and consequences of METH and MDMA toxicity using approaches that span cellular to behavioral methods. Possible mechanisms that are being examined include impairments of the mitochondrial electron transport chain, glutamate derived reactive oxygen species, activation of calcium-dependent intracellular proteins, neuroinflammation, and measures of cell death in select brain regions involved in movement. An animal model is currently being established to assess the functional consequences of damage to cells in the motor output pathway of the extrapyramidal motor system.
Stress and Vulnerability to Methamphetamine and MDMA Toxicity
Environmental stress and drug abuse are inextricably linked. We are examining how chronic psychological stress can alter the neurochemical, physiological, and behavioral consequences of the amphetamines. Conversely, we also are conducting experiments that evaluate how prior exposure to the amphetamines can alter the neurochemical, neuroanatomical, and behavioral effects of chronic stress. Various limbic and motor areas of the brain are being examined for their roles in the dangerous interplay between stress and amphetamines on learning/memory and anxiety.
Drugs of Abuse and the Blood-Brain-Barrier
|References (partial list):|
Matuszewich, L., Filon, M.E., Finn, D.A., and Yamamoto, B.K. Altered forebrain neurotransmitter responses to immobilization stress following 5-HT depletions with MDMA. Neuroscience 110: 41-48, 2002.
Mark, K.A., Soghomonian, J-J, Yamamoto, B.K. High-Dose Methamphetamine Acutely Activates the Striatonigral Pathway to Increase Striatal Glutamate and Mediate Long-term Dopamine Toxicity. Journal of Neuroscience 24: 11449-11456, 2004.
Matuszewich, L, and Yamamoto, B.K. Long-lasting effects of chronic stress on DOI-induced hyperthermia. Psychopharmacology 169: 169-175, 2003.
Bankson, M.G. and Yamamoto, B.K. Serotonin-GABA interactions modulate MDMA-induced mesolimbic dopamine release. J. Neurochemistry 91: 852-859, 2004.
Brown, J. and Yamamoto, B. Effects of amphetamines on mitochondrial function: role of free radicals and oxidative stress. Pharmacology and Therapeutics 99: 45-53, 2003.
Matuszewich, L, and Yamamoto, B.K. Chronic stress augments the acute and long-term effects of methamphetamine. Neuroscience 124: 637-646, 2004.
Eyerman, D and Yamamoto, B.K. Lobeline attenuates methamphetamine induced changes in VMAT-2 immunoreactivity and monoamine depletions in the striatum. J. Pharmacology and Experimental Therapeutics 312: 160-169, 2005.
Darvesh A. S., Yamamoto B. K. and Gudelsky, G. A. Evidence for the involvement of nitric oxide in 3,4-methylenedioxymethamphetamine-induced serotonin depletion in the rat brain. J. Pharmacology and Experimental Therapeutics 312: 694-701, 2005.
Broom, S.L. and Yamamoto, B.K. Effects of Subchronic Methamphetamine Exposure on Basal DA and Stress-induced Dopamine Release in the Nucleus Accumbens Shell of Rats. Psychopharmacology, 181:467-76, 2005.
Brown, J.M., Quinton, M.S. and Yamamoto, B.K. Methamphetamine-Induced inhibition of mitochondrial complex II: Roles of glutamate and peroxynitrite. J. Neurochemistry 95: 429-436, 2005.
Staszewski, R.D. and Yamamoto, B.K. Methamphetamine-induced spectrin proteolysis in the rat striatum. J. Neurochemistry 96: 1267-1276, 2006.
Breier, J.M., Bankson, M.G., and Yamamoto, B.K. L-Tyrosine contributes to (+)-3,4-Methylenedioxymethamphetamine (MDMA)-induced serotonin depletions. J. Neuroscience, 26: 290-299, 2006.
Hatzipetros, T and Yamamoto, B.K. Dopaminergic and GABAergic Modulation of Glutamate Release from Rat Subthalamic Nucleus Efferents to the Substantia Nigra. Brain Research, 1076: 60-67, 2006.
Quinton, M.S. and Yamamoto, B.K. Causes and Consequences of Methamphetamine and MDMA Toxicity. Am. Association of Pharmaceutical Sciences Journal 8: E337-E347, 2006.
Cunningham, J.I. and Yamamoto, B.K. Interactions Between Stress and MDMA: Implications for Neurotoxicity. Cell Science Reviews 3: 198-221, 2006.
Yamamoto, B.K. and Bankson, M.G. Amphetamine Neurotoxicity: Cause and Consequence of Oxidative Stress. Critical Reviews in Neurobiology 17: 87-117, 2005.
Amato, J.L. and Yamamoto, B.K. Prior Exposure to Chronic Stress and MDMA Potentiates Mesoaccumbens Dopamine Release Mediated by the 5HT1B Receptor. Neuropsychopharmacology, 32: 946–954, 2007.
Tata, D and Yamamoto, B.K. Interactions between Methamphetamine and Psychological Stress: Role of Glutamate, Oxidative Stress and Mitochondrial Dysfunction. Addiction, 102 (Suppl 1): 49-60, 2007.
Raudensky, J. and Yamamoto, B.K. Effects of chronic unpredictable stress and methamphetamine on hippocampal glutamate function. Brain Research 1135:129-35, 2006.
Raudensky, J. and Yamamoto, B.K. Effects of chronic unpredictable stress on monoamine transporter immunoreactivity and methamphetamine-induced dopamine release in the nucleus accumbens shell. Synapse 61: 353-355, 2007.
Broom, S.L. and Yamamoto. Role of Norepinephrine in Substance Abuse. In: Brain Norepinephrine: Neurobiology and Therapeutics, eds. Gregory Ordway, Michael Schwartz and Alan Frazer. Cambridge University Press; Cambridge, UK, 2007.
Quinton, M.S. and Yamamoto, B.K. Neurotoxic Effects of Chronic Stress in the Striatum of Methamphetamine-Exposed Rats. Psychopharmacology 193:341-50, 2007.
Hatzipetrros, T., Raudensky, J., Soghomonion, J-J, and Yamamoto, B.K. Haloperidol Treatment After High Dose Methamphetamine Administration is Excitotoxic to GABA Cells in the Substantia Nigra Pars Reticulata. J. Neuroscience 27: 5895-5902, 2007.
Mark, K.A., Russek, S.J. and Yamamoto, B.K. Dynamic Changes in Vesicular Glutamate Transporter (VGLUT1) Function and Expression Related to Methamphetamine-Induced Glutamate Release. J. Neuroscience 27: 6823-6831, 2007.
Tata, D, Raudensky, J, and Yamamoto, B.K. Augmentation of Methamphetamine-induced Toxicity in the Striatum by Unpredictable Stress: Role of Hyperthermia. European Journal of Neuroscience 26: 739-748, 2007.
Eyerman, D.J. and Yamamoto, B.K. A Rapid Oxidation and Persistent Decrease in the Vesicular Monoamine Transporter 2 after Methamphetamine, J. Neurochemistry 103: 1219-1227, 2007.
Tata, D. and Yamamoto, B.K. Chronic Stress Enhances Methamphetamine-Induced Extracellular Glutamate and Excitotoxicity in the Rat Striatum, Synapse 62:325-336, 2008.
Gudelsky G.A and Yamamoto, B.K. Actions of 3,4-Methylenedioxymethamphetamine (MDMA) on Cerebral Dopaminergic, Serotonergic and Cholinergic Neurons. Pharmacology, Biochemistry, and Behavior, 90: 198-207, 2008.
Yamamoto, B.K. and Raudensky J. The Role of Oxidative Stress, Metabolic Compromise, and Inflammation in Neuronal Injury Produced by Amphetamine-Related Drugs of Abuse. J. Neuroimmune Pharmacology, 3: 203-217, 2008. PMID: 18709468
Johnson, B. N. and Yamamoto, B.K. MDMA (Ecstasy). In: Gale Encyclopedia of Drugs, Alcohol & Addictive Behavior, 3rd edition., Macmillan Press, Henry R. Kranzler, Pamela Korsmeyer eds., 2008.
Johnson, B.N. and Yamamoto, B.K. Chronic Unpredictable Stress Augments +3,4-Methylenedioxymethamphetamine (MDMA)-induced Monoamine Depletions: The Role of Corticosterone. Neuroscience 159 1233–1243, 2009.
Bhide, N.S., Lipton, J, Cunningham, J., Yamamoto, B.K. and Gudelsky, G.A. Repeated Exposure to MDMA Provides Neuroprotection Against Subsequent MDMA-induced Serotonin Depletion in Brain, Brain Research 1286: 32-41, 2009.
Cunningham, J, Raudensky, J, Tonkiss, J, and Yamamoto, B.K. MDMA Pretreatment Leads to Mild Chronic Unpredictable Stress-induced Impairments in Spatial learning. Behavioral Neuroscience, 123:1076-84, 2009.
Doyle, J.R. and Yamamoto, B.K. Serotonin 2 receptor modulation of hyperthermia, corticosterone, and hippocampal serotonin depletions following serial exposure to chronic stress and methamphetamine. Psychoneuroendocrinology 35: 629-622, 2010 PMID 19879056
Northrop, N.A. and Yamamoto, B.K. Neuroimmune Pharmacology from a Neuroscience Perspective. Journal of Neuroimmune Pharmacology, 6: 10-19, 2011. PMID 20717737
Northrop, N.A., Smith, L.P., Yamamoto, B.K. and Eyerman, D.J. Regulation of Glutamate Release by Alpha 7 Nicotinic Receptors: Differential Role in Methamphetamine-Induced Damage to Dopaminergic and Serotonergic Terminals. Journal of Pharmacology and Experimental Therapeutics 336: 900-907, 2011. PMID 21159748
Moszczynska, A. and Yamamoto, B.K. Methamphetamine oxidatively damages parkin and decreases the activity of 26S proteasome in vivo. Journal of Neurochemistry, 116: 1005-1017, 2011. PMID: 21166679
Natarajan, R. and Yamamoto, B.K. The Basal Ganglia as a Substrate for the Multiple Actions of Amphetamines. Basal Ganglia 1: 49-57, 2011. PMID 21804952
Yamamoto, B.K. and Chen, Fu-Chen Methamphetamine-induced oxidation of proteins and alterations in protein processing. Neuropsychopharmacology, 37: 298-299, 2012. PMID: 22157863
Northrop, N and Yamamoto, B.K. Persistent Neuroinflammatory Effects of Serial Exposure to Chronic Stress and Methamphetamine on the Blood Brain Barrier, Journal of Neuroimmune Pharmacology 7: 951-968, 2012
Halpin, L. and Yamamoto, B.K. Peripheral ammonia as a mediator of methamphetamine neurotoxicity. Journal of Neuroscience 32(38):13155–13163, 2012. PMID: 22993432
Peritore, C.S., Ho, A., Yamamoto, B.K. and Schaus, S.E. Resveratrol attenuates L-dopa-induced hydrogen peroxide toxicity in neuronal cells, Neuroreport 23: 989-994, 2012.
Stansley, B.J. and Yamamoto, B.K. L-dopa-induced dopamine synthesis and oxidative stress in serotonergic cells. Neuropharmacology 67: 243-251, 2013.
Anneken, J.H., Cunningham, J.I., Collins, S.A., Yamamoto, B.K. and Gudelsky, G.A. MDMA increases glutamate release and reduces parvalbumin-positive GABAergic cells in the dorsal hippocampus of the rat: role of cyclooxygenase. J. Neuroimmune Pharmacol. 8 :58-65, 2013. PMID: 23179355
Huff, C, Bhide, N, Schroering, A, Yamamoto, B.K., Gudelsky, G.A. Effect of repeated exposure to MDMA on the function of the 5-HT transporter as assessed by synaptosomal 5-HT uptake. Brain Res. Bull. 91: 52-57, 2013. PMID: 23318273
Northrop, N.A. and Yamamoto, B.K. Cyclooxygenase activity contributes to the monoaminergic
damage caused by serial exposure to stress and methamphetamine. Neuropharmacology
72: 96-105, 2013. PMID: 23643743
Halpin, L.E. and Yamamoto, B.K. Ammonia Mediates Methamphetamine-Induced Increases in Glutamate and Excitotoxicity. Neuropsychopharmacology, 39: 1031-1038, 2014. PMID: 24165886
Halpin, L.E., Collins, S.A. and Yamamoto, B.K. Neurotoxicity of Methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sciences, 97: 37-44, 2014. PMID: 23892199
Stansley, B. and Yamamoto, B.K. Chronic L-dopa decreases serotonin neurons in a sub-region of the dorsal raphe nucleus, Journal of Pharmacology and Experimental Therapeutics, 351:440-447, 2014. PMID 25212217
Poddar, N, Zano, S., Natarajan, R., Yamamoto B., and Viola, R.E. Enhanced brain distribution of modified aspartoacylase. Molecular Genetics and Metabolism 113: 219-224, 2014 PMID: 25066302
Northrop, N.A. and Yamamoto, B.K. Methamphetamine neurotoxicity and neuroinflammatory processes. In: Neuroinflammation and Neurodegeneration, P.K. Peterson and M. Taborek, eds., Springer, pp. 443-462, 2014