Bryan K. Yamamoto, Ph.D.
Robert B. Forney Professor of Toxicology
Professor and Chair of Pharmacology & Toxicology
Ph.D. Syracuse University, Syracuse, NY (1981)
Postdoc University of Colorado Health Sciences Center (1984)
Mechanisms of Drugs of Abuse, Stress and Brain Injury.
Our lab has 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 and cognition.
In addition, cultures of serotonin 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.
Environmental stress and drug abuse are inextricably linked. In other projects, we are examining how chronic psychological stress alone can produce long-term changes in serotonin transmission and 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.
Additional studies are underway to examine how stimulant drugs of abuse interact with chronic stress to alter the permeability of the blood-brain barrier thereby damaging the brain’s natural defense against the invasion of toxins. Anatomical and protein biochemical approaches are being used to assess the permeability of the blood brain barrier after drugs and stress. As shown, FITC dextran extravasation from capillaries is evident after METH.
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
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.
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
Staszewski, R.D. and Yamamoto, B.K. Methamphetamine-induced spectrin proteolysis in the rat striatum. J. Neurochemistry 96: 1267-1276, 2006. PMID16417574
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.
Hatzipetros, 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.
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
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. PMCID: PMC2677628
Natarajan, R. and Yamamoto, B.K. The Basal Ganglia as a Substrate for the Multiple Actions of Amphetamines. Basal Ganglia 1: 49-57, 2011. PMCID: PMC3144568
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. PMCID: PMC3610410
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. PMCID: PMC3061539
Halpin, L. and Yamamoto, B.K. Peripheral ammonia as a mediator of methamphetamine neurotoxicity. Journal of Neuroscience 32: 13155–13163, 2012. PMCID: PMC3464918
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. PMCID: PMC3612836
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. Journal of Neuroimmune Pharmacology 8: 58-65, 2013. PMID: PMC3587367
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. PMCID: PMC3696421
Halpin, L.E. and Yamamoto, B.K. Ammonia Mediates Methamphetamine-Induced Increases in Glutamate and Excitotoxicity. Neuropsychopharmacology, 39: 1031-1038, 2013. PMCID: PMC3924538
Stansley, B.J. and Yamamoto, B.K. L-dopa-induced dopamine synthesis and oxidative stress in serotonergic cells. Neuropharmacology 67: 243-251, 2013. PMCID: PMC3638241
Weber G., Johnson B., Yamamoto, B.K. and Gudelsky, G.A. Effects of stress and MDMA on hippocampal gene expression. Biomedical Research International, 214: Article 141396, 2014 http://dx.doi.org/10.1155/2014/141396. PMCID: PMC3910535
Stansley, B.J. 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
Anneken, J, Collins, S.A., Yamamoto, B.K., and Gudelsky, G.A. MDMA and Glutamate: Implications for hippocampal toxicity. In: Neuropathology of Drug Addictions and Substance Misuse, Elsevier, 2014
Northrop, N.A. and Yamamoto, B.K. Methamphetamine Effects on Blood-Brain Barrier Structure and Function, Frontiers in Neuroscience-Neuropharmacology, 9: 69, 2015. http://dx.doi.org/10.3389/fnins.2015.00069
Collins, S.A., Gudelsky, G.A. and Yamamoto, B.K. MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2a and NMDA receptors. Eur. J. Pharmacology, 761:95-100, 2015.
Das, S.C. Yamamoto, B.K., Hristov, A.M, and Sari Y. Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate level through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring (P) rats. Neuropharmacology 97:67-74, 2015