Department of Pharmacology & Toxicology

Annette Fleckenstein

Professor of Pharmacology and Toxicology

Annette E. FleckensteinTitle: Professor of Pharmacology and Toxicology
Email address:

Education and Training:

  • B.S. 1988, Western Michigan University
  • M.S. 1990, Western Michigan University
  • Ph.D. 1994, Michigan State University
  • Postdoctoral Fellow 1994-1995, National Institutes of Health - National Institute on Drug Abuse, Add

Research Interests:

Psychostimulants of abuse can cause persistent damage to dopaminergic and/or serotonergic neurons in rodents, non-human primates and humans. In particular, methamphetamine administration causes persistent dopaminergic deficits that, in part, resemble deficits occurring in Parkinson's disease. Dr. Fleckenstein's laboratory investigates receptor-mediated and subcellular mechanisms contributing to these deficits. A variety of techniques are employed including radioligand-binding and monoamine uptake assays, Western blotting and related techniques, and the application of high performance liquid chromatography to assess enzyme activity, oxygen radical formation, and biogenic amine concentrations in the brain.

Several research projects, each funded by the National Institute of Drug Abuse or Johnson and Johnson, are ongoing in Dr. Fleckenstein's laboratory. The first investigates mechanisms underlying the neurotoxic effects of methamphetamine, with a particular emphasis on the role of aging and reactive oxygen species in effecting this process. The second investigates the role of vesicular trafficking in mediating the differential neurotoxic impact of methamphetamine and cocaine. Another project investigates the differential acute and persistent effects of methylenedioxymethamphetamine ("ecstasy"), amphetamine and methamphetamine on plasmalemmal dopamine, plasmalemmal serotonin, and vesicular monoamine transport, with a particular focus on subcellular mechanisms regulating the internalization, dimerization and/or trafficking of these proteins. The final project investigates the differential impact of methylphenidate and amphetamine on vesicular monoamine transport. In particular, this project focuses on mechanisms whereby methylphenidate traffics vesicles and may thereby afford protection against certain neurodegenerative processes.

Selected Publications:

  • Volz, T.J., Hanson, G.R., Fleckenstein, A.E., 2006.  Measurement of kinetically-resolved vesicular dopamine uptake and efflux using rotating disk electrode voltammetry.  J. Neurosci. Methods 155:109-115.
  • Rau, K.S., Birdsall, E., Baucum, A.J., Adair, B.P., Bitter, R., Gibb, J.W., Hanson, G.R., Fleckenstein, A.E., 2006.   Methamphetamine administration reduces hippocampal VMAT-2. J. Pharmacol. Exp. Ther. 318:676-682.
  • Volz, T.J., Hanson, G.R., Fleckenstein, A.E., 2006. Kinetic analysis of age-dependent changes in vesicular monoamine transporter-2 function. Synapse 60:474-477.
  • Rau, K.S., Truong, J.T., Fleckenstein, A.E., Hanson, G.R., 2006. Age-dependent effects of methamphetamine on VMAT-2. Ann. N. Y. Acad. Sci. 1074: 154-159.
  • Riddle, E.L., Fleckenstein, A.E., Hanson G.R., 2006. Mechanisms of methamphetamine-induced dopaminergic toxicity.  AAAPs J 8:E413-418.
  • Danaceau, J.P., Deering, C.E., Day, J.E., Smeal, S.J., Johnson-Davis, K.L., Fleckenstein, A.E., Wilkins, D.G.  2007.  Persistence of tolerance to methamphetamine-induced monoamine deficits.  Eur. J. Pharmacol. 559:46-54.
  • Riddle, E.L., Hanson, G.R., Fleckenstein, A.E. 2007. Amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2.  Eur. J. Pharmacol. 571:25-28.
  • Volz, T.J., Farnsworth, S.J., King, J.L., Riddle, E.L., Hanson, G.R., Fleckenstein, A.E. 2007. Methylphenidate administration alters vesicular monoamine transporter-2 function in cytoplasmic and membrane-associated vesicles. J. Pharmacol. Exp. Ther. 323:738-745.
  • Volz, T.J., Hanson, G.R., Fleckenstein, A.E. 2007.  The role of the plasmalemmal dopamine and vesicular monoamine transporters in methamphetamine-induced dopaminergic deficits.  J. Neurochem. 101:883-888.
  • Volz, T.J., Fleckenstein, A.E., Hanson, G.R. 2007.  Methamphetamine-induced alterations in monoamine transport: Implications for neurotoxicity, neuroprotection and treatment. Addiction 102 Suppl 1:44-8.
  • Fleckenstein, A.E., Volz, T.J., Riddle, E.L., Hanson, G.R. 2007.  New insights into the mechanism of action of amphetamines. Ann. Rev. Pharm. Tox. 47: 681-698.
  • Chu, P.W.,  Seferian, K.S., Birdsall, E., Truong, J.G., Riordan, J.A., Metcalf, C.S., Hanson, G.R., Fleckenstein, A.E., 2008.  Differential regional effects of methamphetamine on dopamine transport.  Eur. J. Pharmacol. (in press).
  • Volz, T.J., Farnsworth, S.J., Rowley, S.D., Hanson, G.R., Fleckenstein, A.E.  2008.  Age-dependent differences in dopamine transporter and vesicular monoamine transporter-2 function and implications for methamphetamine neurotoxicity.  Synapse (in press).   
  • Volz, T.J., Farnsworth, S.J., Hanson, G.R., Fleckenstein, A.E.  2008  Methylphenidate-induced increases in vesicular dopamine sequestration and dopamine release in the straitum: The role of muscarinic and dopamine D2 receptors.  J. Pharmacol. Exp. Ther. (in press).
  • Volz, T.J., Farnsworth, S.J., Hanson, G.R., Fleckenstein, A.E. Methylphendiate-induced alterations in synaptic vesicle trafficking and activity: Functional consequences and therapeutic implications.  Ann. N.Y. Acad. Sci. (in press).
  • Fleckenstein, A.E., Volz, T.J. Hanson, G.R. 2008. Psychostimulants and the vesicular monoamine transporter-2.  Neuropharmacology (in press).