ANNETTE E. FLECKENSTEIN
Annette Fleckenstein Professor of Pharmacology and Toxicology

Neurobiology of Disease
Cellular Neuroscience

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, Addiction Research Center.

RESEARCH:

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 mechansims contributing to these deficits. A variety of techniques are employed including radioligand-binding and monoamine uptake assays, western blotting, 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 are ongoing in Dr. Fleckenstein's laboratory. One involves investigating mechanisms underlying the neurotoxic effects of methamphetamine, with a particular emphasis on the role of aging and reactive oxygen species in mediating this process. Another investigates the role of vesicular trafficking in mediating the differential neurotoxic impact of psychostimulants. A third project investigates the differential acute and persistent effects of psychostimulants on plasmalemmal dopamine, plasmalemmal serotonin and vesicular monoamine transport, with a particular emphasis on subcellular mechanisms regulating the internalization, dimerization and/or trafficking of these proteins.

Selected Publications

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.

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., 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.

Truong, J.G., Wilkins, D.G., Baudys, J., Crouch, D.J., Johnson-Davis, K.L., Gibb, J.W., Hanson, G.R., and Fleckenstein, A.E. (2005) Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: Implications for neurotoxicity. J. Pharmacol. Exp. Ther., 314(3):1087-1092.

Rau, K.S., Birdsall, E., Hanson, J.E., Johnson-Davis, K.L., Carroll, F.I., Wilkins, D.G., Gibb, J.W., Hanson, G.R., and Fleckenstein, A.E. (2005) Bupropion increases striatal vesicular monoamine transport. Neuropharmacol., Nov;49(6):820-830.

Hanson, G.R., Rau, K.S., and Fleckenstein, A.E. (2004) The methamphetamine experience: A NIDA partnership. Neuropharmacology, 47 Suppl 1:92-100.

Truong, J.G., Newman, A.H., Hanson, G.R., and Fleckenstein, A.E. (2004) Dopamine D2 receptor activation increases vesicular dopamine uptake and redistributes vesicular monoamine transporter-2 protein. Eur J Pharmacol., 504:27-32.

Hanson, G.R., Sandoval, V., Riddle, E., and Fleckenstein, A.E. (2004) Psychostimulants and vesicle trafficking: a novel mechanism and therapeutic implications. Ann N Y Acad Sci., 1025:146-150.

Truong, J.T., Hanson, G.R., and Fleckenstein, A.E. (2004) Apomorphine increases vesicular dopamine uptake: Implications for treatment of Parkinson's Disease. Eur. J. Pharmacol., 492:143-147.

Johnson-Davis, K.L., Truong, J.G., Fleckenstein, A.E., and Wilkins, D.G. (2004) Alterations in vesicular dopamine uptake contribute to tolerance to the neurotoxic effects of methamphetamine. J. Pharmacol. Exp. Ther., 309:578-586.

Baucum A.J. 2nd, Rau K.S., Riddle E.L., Hanson G.R., and Fleckenstein A E. (2004) Methamphetamine increases dopamine transporter higher molecular weight complex formation via a dopamine- and hyperthermia-associated mechanism. J Neurosci., 24:3436-3443.

Johnson-Davis, K.L., Fleckenstein, A.E., and Wilkins, D.G. (2003) The role of hyperthermia and metabolism as mechanisms of tolerance to methamphetamine. Eur. J. Pharmacol., 482:151-154.

Hanson, G.R., Sandoval, V., Riddle, E.L., and Fleckenstein, A.E. (2003) Psychostimulants and Vesicle Trafficking: A Novel Mechanism and Therapeutic Implications Ann. N. Y. Acad. Sci.

Fleckenstein, A.E., and Hanson, G.R. (2003) Impact of psychostimulants on vesicular monoamine transporter function. Eur. J. Pharmacol., 479:283-289.

Truong, J.T., Rau, K.S., Hanson, G.R., and Fleckenstein, A.E. (2003) Pramipexole rapidly redistributes VMAT-2 protein. Eur. J. Pharmacol., 474:223-236.

Ugarte, Y.V., Riddle, E.L., Hanson, G.R., and Fleckestein, A.E. (2003) Methamphetamine rapidly decreases mouse vesicular dopamine transport. Eur. J. Pharmacol., 472:165-171.

Sandoval, V.S., Riddle, E.L., Hanson, G.R., and Fleckenstein, A.E. (2003) Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits. J. Pharmacol. Exp. Ther., 304:1181-1187.

Riddle, E.L., Rau, K.S., Tophan, M.K., Hanson, G.R., and Fleckenstein, A.E. (2003) Ceramide-induced alterations in dopamine transporter function. Eur. J. Pharmacol, 458:31-36.

Fleckenstein, A.E., Hanson, G.R. (2003) Psychostimulants and the Vesicular Monoamine Transporter, Eur. J. Pharmacol., 479:283-289.

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