This revised application for a Senior Scientist Award (K05) is submitted to enable the applicant to continue engaging in drug abuse research for the next five years. Research in the applicant's laboratory focuses on substituted amphetamine derivatives (MDMA, methamphetamine) and their propensity to selectively damage brain serotonin and/or dopamine neurons in animals and, possibly, humans. The long-term goals of this research are to better define risks and consequences of substituted amphetamine exposure in humans, and to further elucidate the role of serotonin and dopamine in the central nervous system (CNS), both in health and disease. In addition, this research seeks to identify the mechanism by which substituted amphetamines damage brain aminergic neurons, as this information may yield insight into the processes underlying neuronal loss in human neurodegenerative conditions. A variety of methods are used to achieve these goals. Studies in isolated systems (gene microarrays, synaptosomes and cultured cells) and intact animals (rodents) explore mechanisms of substituted amphetamine neurotoxicity, identify critical molecular requirements for the expression of neurotoxicity, and characterize the short- and long-term responses of serotonin and dopamine neurons to substituted amphetamine neurotoxicity. Studies in nonhuman primates seek to more accurately gauge the risk that substituted amphetamines pose to humans and to develop and validate methods for detecting the consequences of substituted amphetamine neurotoxicity in humans. Studies in humans, which include molecular PET imaging, pharmacologic challenges, neuropsychiatric evaluations, cognitive testing and polysomnographic evaluations, are designed to determine whether humans who use substituted amphetamines develop neurotoxicity and, if so, the functional consequences. By decreasing the amount of time required for clinical work, teaching, administration and other departmental duties, this K05 award will enable the applicant to optimize research productivity, continue training junior faculty and fellows in his laboratory, and participate in national and international forums intended to educate the public regarding the neurotoxic potential of substituted amphetamines.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
5K05DA017964-02
Application #
7052010
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Frankenheim, Jerry
Project Start
2005-04-15
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$128,913
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Slezak, Jonathan M; Mueller, Melanie; Ricaurte, George A et al. (2018) Pharmacokinetic and pharmacodynamic analysis of d-amphetamine in an attention task in rodents. Behav Pharmacol 29:551-556
Mueller, Melanie; Yuan, Jie; Maldonado Adrian, Concepcion et al. (2011) Inhibition of 3,4-methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4-dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: implications for mechanisms of neurotoxicity. Synapse 65:983-90
Neudorffer, Anne; Mueller, Melanie; Martinez, Claire-Marie et al. (2011) Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate. Chem Res Toxicol 24:968-78
Mueller, Melanie; Kolbrich-Spargo, Erin A; Peters, Frank T et al. (2009) Hydrolysis of 3,4-methylenedioxymethamphetamine (MDMA) metabolite conjugates in human, squirrel monkey, and rat plasma. Anal Bioanal Chem 393:1607-17
Mueller, Melanie; Kolbrich, Erin A; Peters, Frank T et al. (2009) Direct comparison of (+/-) 3,4-methylenedioxymethamphetamine (""ecstasy"") disposition and metabolism in squirrel monkeys and humans. Ther Drug Monit 31:367-73
Mueller, Melanie; Peters, Frank T; Ricaurte, George A et al. (2008) Liquid chromatographic-electrospray ionization mass spectrometric assay for simultaneous determination of 3,4-methylenedioxymethamphetamine and its metabolites 3,4-methylenedioxyamphetamine, 3,4-dihydroxymethamphetamine, and 4-hydroxy-3-methoxymethampheta J Chromatogr B Analyt Technol Biomed Life Sci 874:119-24
McCann, Una D; Szabo, Zsolt; Vranesic, Melin et al. (2008) Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/-)3,4-methylenedioxymethamphetamine (""ecstasy"") users: relationship to cognitive performance. Psychopharmacology (Berl) 200:439-50
Mueller, Melanie; Peters, Frank T; Ricaurte, George A et al. (2007) Validated liquid chromatographic-electrospray ionization mass spectrometric assay for simultaneous determination of 3,4-methylenedioxymethamphetamine and its metabolites 3,4-methylenedioxyamphetamine, 3,4-dihydroxymethamphetamine, and 4-hydroxy-3-methoxym J Chromatogr B Analyt Technol Biomed Life Sci 855:262-70
McLane, Michael W; Hatzidimitriou, George; Yuan, Jie et al. (2007) Heating induces aggregation and decreases detection of serotonin transporter protein on western blots. Synapse 61:875-6
Yuan, Jie; Hatzidimitriou, George; Suthar, Pranav et al. (2006) Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys. J Pharmacol Exp Ther 316:1210-8

Showing the most recent 10 out of 12 publications